Halogenated quinazolin-thf-amines as pde1 inhibitors

ABSTRACT

The present invention provides halogenated quinazolin-THF-amines as PDE1 inhibitors and their use as a medicament, in particular for the treatment of neurodegenerative disorders and psychiatric disorders.

FIELD OF THE INVENTION

The present invention provides compounds that are PDE1 enzyme inhibitorsand their use as a medicament, in particular for the treatment ofneurodegenerative disorders and psychiatric disorders. The presentinvention also provides pharmaceutical compositions comprising compoundsof the invention and methods of treating disorders using the compoundsof the invention.

BACKGROUND OF THE INVENTION

Throughout this application, various publications are referenced infull. The disclosures of these publications are hereby incorporated byreference into this application to describe more fully the state of theart to which this invention pertains.

The second messenger cyclic Nucleotides (cNs), cyclic adenosinemonophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) play amajor role in intracellular signal transduction cascade, by regulatingcN-dependent protein kinases (PKA and PKG), EPACs (Exchange ProteinActivated by cAMP), phosphoprotein phosphatases, and/or cN-gated cationchannels. In neurons, this includes the activation of cAMP- andcGMP-dependent kinases and subsequent phosphorylation of proteinsinvolved in acute regulation of synaptic transmission as well as inneuronal differentiation and survival. Intracellular concentrations ofcAMP and cGMP are strictly regulated by the rate of biosynthesis bycyclases and by the rate of degradation by phosphodiesterases (PDEs, EC3.1.4.17). PDEs are bimetallic hydrolases that inactivate cAMP/cGMP bycatalytic hydrolysis of the 3′-ester bond, forming the inactive5′-monophosphate. Since PDEs provide the only means of degrading thecyclic nucleotides cAMP and cGMP in cells, PDEs play an essential rolein cyclic nucleotide signalling. The catalytic activities of PDEsprovide for breakdown of cNs over a spectrum of concentrations in allcells, and their varied regulatory mechanisms provide for integrationand crosstalk with myriad signalling pathways. Particular PDEs aretargeted to discrete compartments within cells where they control cNlevel and sculpt microenvironments for a variety of cN signalosomes(Sharron H. Francis, Mitsi A. Blount, and Jackie D. Corbin. Physiol Rev2011, 91: 651-690).

On the basis of substrate specificity, the PDE families can be dividedinto three groups: 1) The cAMP-specific PDEs, which include PDE4, PDE7,and PDE8, 2) the cGMP-selective enzymes PDES and PDE9, and 3) thedual-substrate PDEs, PDE1, PDE2, PDE3, as well as PDE10 and PDE11.

Previously named calmodulin-stimulated PDE (CaM-PDE), PDE1 is unique inthat it is Ca²⁺-dependently regulated via calmodulin (CaM, a 16 kDaCa²⁺-binding protein) complexed with four Ca²⁺ (for review, Sharron H.Francis, Mitsi A. Blount, and Jackie D. Corbin. Physiol Rev 2011, 91:651-690). Thus, this family represents an interesting regulatory linkbetween cyclic nucleotides and intracellular Ca²⁺. The PDE1 family isencoded by three genes: PDE1A (mapped on human chromosome 2q32), PDE1B(human chromosome location, hcl: 12q13) and PDE1C (hcl: 7p14.3). Theyhave alternative promoters and give rise to a multitude of proteins byalternative splicing which differ in their regulatory properties,substrate affinities, specific activities, activation constants for CaM,tissue distribution and molecular weights. More than 10 human isoformsare identified. Their molecular weights vary from 58 to 86 kDa permonomer. The N-terminal regulatory domain that contains two Ca²⁺/CaMbinding domains and two phosphorylation sites differentiate theircorresponding proteins and modulate their biochemical functions. PDE1 isa dual substrate PDE and the PDE1C-subtype has equal activity towardscAMP and cGMP (Km≈1-3 μM), whereas the subtypes PDE1A and PDE1B has apreference for cGMP (Km for cGMP≈1-3 μM and for cAMP≈10-30 μM).

The PDE1 subtypes are highly enriched in the brain and locatedespecially in the striatum (PDE1B), hippocampus (PDE1A) and cortex(PDE1A) and this localization is conserved across species (Amy Bernardet al. Neuron 2012, 73, 1083-1099). In the cortex, PDE1A is presentmainly in deep cortical layers 5 and 6 (output layers), and used as aspecificity marker for the deep cortical layers. PDE1 inhibitors enhancethe levels of the second messenger cNs leading to enhanced neuronalexcitability.

Thus, PDE1 is a therapeutic target for regulation of intracellularsignalling pathways, preferably in the nervous system and PDE1inhibitors can enhance the levels of the second messengers cAMP/cGMPleading to modulation of neuronal processes and to the expression ofneuronal plasticity-related genes, neurotrophic factors, andneuroprotective molecules. These neuronal plasticity enhancementproperties together with the modulation of synaptic transmission makePDE1 inhibitors good candidates as therapeutic agents in manyneurological and psychiatric conditions. The evaluation of PDE1inhibitors in animal models (for reviews see e.g. Blokland et al. ExpertOpinion on Therapeutic Patents (2012), 22(4), 349-354; and Medina, A. E.Frontiers in Neuropharmacology (2011), 5(Feb.), 21) have suggested thepotential for the therapeutic use of PDE1 inhibitors in neurologicaldisorders, like e.g. Alzheimer's, Parkinson's and Huntington's Diseasesand in psychiatric disorders like e.g. Attention Deficit HyperactivityDisorder (ADHD), restless leg syndrome, depression, narcolepsy,cognitive impairment and cognitive impairment associated is withschizophrenia (CIAS). There have also been patent applications claimingthat PDE1 inhibitors are useful in diseases that may be alleviated bythe enhancement of progesterone-signalling such as female sexualdysfunction e.g. WO-2010065153.

SUMMARY OF THE INVENTION

PDE1 enzymes are expressed in the Central Nervous System (CNS), makingthis gene family an attractive source of new targets for the treatmentof psychiatric and neurodegenerative disorders.

The compounds of the invention may offer alternatives to currentmarketed treatments for neurodegenerative and/or psychiatric disorders,which are not efficacious in all patients. Hence, there remains a needfor alternative methods of treatment.

The objective of the present invention is to provide compounds that arePDE1 inhibitors, and as such are useful to treat neurodegenerativedisorders and psychiatric disorders. In a preferred embodiment thecompounds are selective PDE1 inhibitors.

Accordingly, the present invention relates to compounds of formula (I)

wherein

X is halogen, preferably fluorine or chlorine or bromine;

R₁ is selected from the group consisting of H and C₁-C₃ alkyl, whereinthe alkyl optionally may be substituted one, two or three times withfluorine;

R₂ is selected from the group consisting of H and C₁-C₄ alkyl, whereinthe C₁-C₄ alkyl optionally is substituted one or more times with one ormore substituents,

R₃ is selected from the group consisting of H and C₁-C₆ alkyl, whereinthe C₁-C₆ alkyl optionally is substituted one or more times with one ormore substituents,

R₄ and R₅ independently of each other are selected from the groupconsisting of H, C₁-C₆ alkyl, optionally is substituted one or moretimes with one or more substituents, C₃-C₆ cycloalkyl, fluorine,chlorine, hydroxy and alkoxy,

R₆ and R₇ independently of each other are selected from the groupconsisting of H and C₁-C₆ alkyl, wherein the C₁-C₆ alkyl optionally issubstituted one or more times with one or more substituents,

R₈ and R₉ independently of each other are selected from the groupconsisting of H and C₁-C₆ alkyl, wherein the C₁-C₆ alkyl optionally issubstituted one or more times with one or more substituents,

and pharmaceutically acceptable acid addition salts of Compound I,racemic mixtures of Compound I, or the corresponding enantiomer and/ordiastereo-isomer of Compound I, and polymorphic forms of Compound I aswell as tautomeric forms of Compound I.

DETAILED DESCRIPTION OF THE INVENTION Embodiments of the Invention

In a first embodiment (E1) the present invention relates to compounds offormula (I) (Compound I)

wherein

R₁ is selected from the group consisting of H and C₁-C₃ alkyl, whereinthe alkyl optionally may be substituted one, two or three times withfluorine;

R₂ is selected from the group consisting of H and C₁-C₄ alkyl

-   -   wherein R₂, when R₂ is a C₁-C₄ alkyl, may form a saturated five        membered aliphatic ring with R₉    -   wherein the C₁-C₄ alkyl optionally is substituted one or more        times with one or more substituents independently selected from        the group consisting of phenyl, monocyclic 5- or 6-membered        heteroaryl, C₃-C₆ cycloalkyl, fluorine, chlorine, and alkoxy of        the form —OR₁₀    -   wherein R₁₀ is C₁-C₅ alkyl;

R₃ is selected from the group consisting of H and C₁-C₆ alkyl

-   -   wherein the C₁-C₆ alkyl optionally is substituted one or more        times with one or more substituents independently selected from        the group consisting of phenyl, monocyclic 5- or 6-membered        heteroaryl, C₃-C₆ cycloalkyl, fluorine, chlorine, and alkoxy of        the form —OR₁₀    -   wherein R₁₀ is C₁-C₅ alkyl;

R₄ and R₅ independently of each other are selected from the groupconsisting of H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, fluorine, chlorine,hydroxy and alkoxy of the form —OR₁₀

-   -   wherein the C₁-C₆ alkyl optionally is substituted one or more        times with one or more substituents independently selected from        the group consisting of phenyl, monocyclic 5- or 6-membered        heteroaryl, C₃-C₆ cycloalkyl, fluorine, chlorine, and alkoxy of        the form —OR₁₀        -   wherein R₁₀ is C₁-C₅ alkyl;

R₆ and R₇ independently of each other are selected from the groupconsisting of H and C₁-C₆ alkyl

-   -   wherein the C₁-C₆ alkyl optionally is substituted one or more        times with one or more substituents independently selected from        the group consisting of C₃-C₆ cycloalkyl, fluorine, chlorine,        and alkoxy of the form —OR₁₀        -   wherein R₁₀ is C₁-C₅ alkyl;

R₈ and R₉ independently of each other are selected from the groupconsisting of H and C₁-C₆ alkyl

-   -   wherein R₉, when R₉ is a C₁-C₆ alkyl, may form a saturated        aliphatic five membered ring with R₂    -   wherein the C₁-C₆ alkyl optionally is substituted one or more        times with one or more substituents independently selected from        the group consisting of C₃-C₆ cycloalkyl, fluorine, chlorine,        and alkoxy of the form —OR₁₀        -   wherein R₁₀ is C₁-C₅ alkyl;    -   and/or pharmaceutically acceptable acid addition salts of        Compound I, racemic mixtures of Compound I, or the corresponding        enantiomer and/or optical isomer of Compound I, and polymorphic        forms of Compound I as well as tautomeric forms of Compound I.

In an embodiment (E2) of (E1) R₂ is H or —CH₃.

In an embodiment (E3) of any of (E1) and (E2) at least one of R₆ and R₇is H.

In an embodiment (E4) of (E3) both R₆ and R₇ are H.

In an embodiment (E5) of (E1) at least four of R₃ to R₉ are H.

In an embodiment (E6) of (E1) when any of R₃, R₄ or R₅ are alkyl, thenat most one of them is substituted at most once with phenyl ormonocyclic 5- or 6-membered heteroaryl.

In an embodiment (E7) of (E1) R₂ and R₉ form a five-membered saturatedaliphatic ringsystem.

In an embodiment (E8) of (E1) R₁ is substituted one time with fluorine.

In an embodiment (E9) of (E1) R₁ is substituted two times with fluorine.

In an embodiment (E10) of (E1) R₁ is substituted three times withfluorine.

In an embodiment (E11) of (E1) X is fluorine.

In an embodiment (E12) of (E1) X is chlorine.

In an embodiment (E13) of any of (E1) to (E12) the compound is selectedfrom the group of compounds listed in Table 1.

In an embodiment (E14) of any of (E1) to (E13) the compound is a PDE1Ainhibitor.

In an embodiment (E15) of any of (E1) to (E13) the compound is a PDE1Binhibitor.

In an embodiment (E16) of any of (E1) to (E13) the compound is a PDE1Cinhibitor.

In an embodiment (E17) the compound of any of (E1) to (E16) is for useas a medicament.

In an embodiment (E18) the compound of any of (E1) to (E16) is use inthe treatment of attention-deficit/hyperactivity disorder (ADHD)

Embodiment (E19): A pharmaceutical composition comprising the compoundof any of (E1) to (E16) and one or more pharmaceutically acceptablecarriers.

Embodiment (E20): A pharmaceutical composition according to (E19) foruse in a method of treatment of attention-deficit/hyperactivity disorder(ADHD)

Embodiment (E21): A compound of any one of (E1) to (E16) for use in amethod for the treatment of attention-deficit/hyperactivity disorder(ADHD)

Embodiment (E22): A compound of any one of (E1) to (E16) for thepreparation of a medicament for use in the treatment ofattention-deficit/hyperactivity disorder (ADHD).

Embodiment (E23): A method of treating a subject suffering ofattention-deficit/hyperactivity disorder (ADHD) which method comprisesadministering an effective amount of a compound of any one (E1) to(E16).

Embodiment (E24): A pharmaceutical composition according to (E19) foruse in a method of treatment of neurodegenerative disorder.

Embodiment (E25): A compound of any one of (E1) to (E16) for use in amethod for the treatment of neurodegenerative disorder.

Embodiment (E26): A compound of any one of (E1) to (E16) for thepreparation of a medicament for use in the treatment ofneurodegenerative disorder.

Embodiment (E27): A method of treating a subject suffering of aneurodegenerative disorder which method comprises administering aneffective amount of a compound of any one (E1) to (E16).

In an embodiment (E28) of any of embodiments (E24) to (E27) theneurodegenerative disorder is selected from the group consisting ofAlzheimer's Disease, Parkinson's Disease and Huntington's Disease or forthe treatment of a psychiatric disorder such as Attention Deficithyperactivity Disorder (ADHD), depression, narcolepsy, cognitiveimpairment and cognitive impairment associated with schizophrenia(CIAS).

Embodiment (E29): Use of a compound of any of claims 1-7 in themanufacture of a medicament for the treatment of a neurodegenerativedisorder, such as Alzheimer's Disease, Parkinson's Disease andHuntington's Disease or for the treatment of a psychiatric disorder suchas Attention Deficit hyperactivity Disorder (ADHD), depression,narcolepsy, cognitive impairment and cognitive impairment associatedwith schizophrenia (CIAS) or a brain disease like restless leg syndrome.

Embodiment (E30): In an embodiment (E30) of (E1) R₁ is H.

Definitions

PDE1 Enzymes

The PDE1 isozyme family includes numerous splice variant PDE1 isoforms.It has three subtypes, PDE1A, PDE1B and PDE1C which divide further intovarious isoforms. In the context of the present invention PDE1 and PDE1enzymes are synonymous and refer to PDE1A, PDE1B and PDE1C enzymes aswell as their isoforms.

Substituents

As used in the context of the present invention, the terms “halo” and“halogen” are used interchangeably and refer to fluorine, chlorine,bromine or iodine.

The terms “C₁-C₃ alkyl”, “C₁-C₄ alkyl”, “C₁-C₅ alkyl” and “C₁-C₆ alkyl”refer to a straight-chain or branched saturated hydrocarbon having fromone to six carbon atoms, inclusive. Examples of such groups include, butare not limited to, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl,2-methyl-2-propyl, 2-methyl-1-butyl, and n-hexyl.

The term “C₃-C₆ cycloalkyl” refers to cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl.

The expression “alkoxy” refers to a straight-chain or branched saturatedalkoxy group having from one to six carbon atoms, inclusive, with theopen valency on the oxygen. Examples of such groups include, but are notlimited to, methoxy, ethoxy, n-butoxy, 2-methyl-pentoxy and n-hexyloxy.

The term “aryl” refers to a phenyl ring, optionally substituted withhalogen, C₁-C₆ alkyl, C₁-C₆ alkoxy or halo(C₁-C₆)alkyl as defined above.

The term “heteroaryl” refers to monocyclic- or polycyclic aromatic ringcomprising carbon atoms, hydrogen atoms, and one or more heteroatoms,preferably, 1 to 3 heteroatoms, independently selected from nitrogen,oxygen, and sulfur. Illustrative examples of heteroaryl groups include,but are not limited to, pyridinyl, pyridazinyl, triazinyl, pyrrolyl,pyrazolyl, imidazolyl, (1,2,3,)- and (1,2,4)-triazolyl, pyrazinyl,pyrimidinyl, tetrazolyl, furanyl, thiophenyl, isoxazolyl, thiazolyl,isoxazolyl, and oxazolyl. A heteroaryl group can be unsubstituted orsubstituted with one or two suitable substituents. Preferably, theheteroaryl of this invention is a monocyclic 5 or 6 membered heteroaryl,wherein the ring comprises 2 to 5 carbon atoms and 1 to 3 heteroatoms,referred to herein as “monocyclic 5 or 6 membered heteroaryl”.

Isomeric Forms

Where compounds of the present invention contain one or more chiralcenters reference to any of the compounds will, unless otherwisespecified, cover any of the enantiomerically or diastereomerically purecompounds as well as mixtures of the enantiomers or diastereomers in anyratio.

For example reference to the compound8-fluoro-7-methoxy-N-(3-methyltetrahydrofuran-3-yl)quinazolin-4-aminewithout any further specification covers(R)-8-fluoro-7-methoxy-N-(3-methyltetrahydrofuran-3-yl)quinazolin-4-amine,(S)-8-fluoro-7-methoxy-N-(3-methyltetrahydrofuran-3-yl)quinazolin-4-amineas well as mixtures of the enantiomers in any ratio, including theracemic mixture(±)8-fluoro-7-methoxy-N-(3-methyltetrahydrofuran-3-yl)quinazolin-4-amine.

Correspondingly, reference to the compound8-fluoro-7-methoxy-N-(2-methyltetrahydrofuran-3-yl)quinazolin-4-aminewithout any further specification covers all four stereoisomericvariants as well as mixtures thereof in any ratio, including the racemicmixtures.

The above also applies where compounds of the invention contain morethan two chiral centers.

PDE1 Inhibitors

In the context of the present invention a compound is considered to be aPDE1 inhibitor if the amount required to reach the IC₅₀ level of PDE1Bis 5 micro molar or less, preferably less than 4 micro molar, such as 3micro molar or less, more preferably 2 micro molar or less, such as 1micro molar or less, in particular 500 nM or less. In preferredembodiments the required amount of PDE1 inhibitor required to to reachthe IC₅₀ level of PDE1B is 400 nM or less, such as 300 nM or less, 200nM or less, 100 nM or less, or even 80 nM or less, such as 50 nM orless, for example 25 nM or less.

Pharmaceutically Acceptable Salts

The present invention also comprises pharmaceutically acceptable saltsof the compounds. Such salts include acid addition salts. Acid additionsalts include salts of inorganic acids as well as organic acids.

Representative examples of suitable inorganic acids includehydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, sulfamic,nitric acids and the like. Representative examples of suitable organicacids include formic, acetic, trichloroacetic, trifluoroacetic,propionic, benzoic, cinnamic, citric, fumaric, glycolic, itaconic,lactic, methanesulfonic, maleic, malic, malonic, mandelic, oxalic,picric, pyruvic, salicylic, succinic, methane sulfonic, ethanesulfonic,tartaric, ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic,gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic,p-aminobenzoic, glutamic, benzenesulfonic, p-toluenesulfonic acids,theophylline acetic acids, as well as the 8-halotheophyllines, forexample 8-bromotheophylline and the like. Further examples ofpharmaceutically acceptable inorganic or organic acid addition saltsinclude the pharmaceutically acceptable salts listed in Berge, S. M. etal., J. Pharm. Sci. 1977, 66, 2, the contents of which are herebyincorporated by reference.

Furthermore, the compounds of this invention may exist in unsolvated aswell as in solvated forms with pharmaceutically acceptable solvents suchas water, ethanol and the like. In general, the solvated forms areconsidered equivalent to the unsolvated forms for the purposes of thisinvention.

Therapeutically Effective Amount

In the present context, the term “therapeutically effective amount” of acompound means an amount sufficient to cure, alleviate or partiallyarrest the clinical manifestations of a given disease and/or itscomplications in a therapeutic intervention comprising theadministration of said compound. An amount adequate to accomplish thisis defined as “therapeutically effective amount”. Effective amounts foreach purpose will depend on the severity of the disease or injury aswell as the weight and general state of the subject. It will beunderstood that determining an appropriate dosage may be achieved usingroutine experimentation, by constructing a matrix of values and testingdifferent points in the matrix, which is all within the ordinary skillsof a trained physician.

In the present context, the term “treatment” and “treating” means themanagement and care of a patient for the purpose of combating acondition, such as a disease or a disorder. The term is intended toinclude the full spectrum of treatments for a given condition from whichthe patient is suffering, such as administration of the active compoundto alleviate the symptoms or complications, to delay the progression ofthe disease, disorder or condition, to relief the symptoms andcomplications, and/or to prevent the condition, wherein prevention is tobe understood as the management and care of a patient for the purpose ofcombating the disease, condition, or disorder and includes theadministration of the active compounds to prevent the onset of thesymptoms or complications. Nonetheless, prophylactic (preventive) andtherapeutic (curative) treatments are two separate aspects of theinvention. The patient to be treated is preferably a mammal, inparticular a human being.

Pharmaceutical Compositions

The present invention further provides a pharmaceutical compositioncomprising a therapeutically effective amount of a compound of formula(I) and a pharmaceutically acceptable carrier or diluent. The presentinvention also provides a pharmaceutical composition comprising atherapeutically effective amount of one of the specific compoundsdisclosed in the Experimental Section herein and a pharmaceuticallyacceptable carrier or diluent.

The compounds of the invention may be administered alone or incombination with pharmaceutically acceptable carriers, diluents orexcipients, in either single or multiple doses. The pharmaceuticalcompositions according to the invention may be formulated withpharmaceutically acceptable carriers or diluents as well as any otherknown adjuvants and excipients in accordance with conventionaltechniques such as those disclosed in Remington: The Science andPractice of Pharmacy, 21^(th) Edition, Gennaro, Ed., Mack PublishingCo., Easton, Pa., 2005.

The pharmaceutical compositions may be specifically formulated foradministration by any suitable route such as oral, rectal, nasal,pulmonary, topical (including buccal and sublingual), transdermal,intracisternal, intraperitoneal, vaginal and parenteral (includingsubcutaneous, intramuscular, intrathecal, intravenous and intradermal)routes. It will be appreciated that the route will depend on the generalcondition and age of the subject to be treated, the nature of thecondition to be treated and the active ingredient.

Pharmaceutical compositions for oral administration include solid dosageforms such as capsules, tablets, dragees, pills, lozenges, powders andgranules. Where appropriate, the compositions may be prepared withcoatings such as enteric coatings or they may be formulated so as toprovide controlled release of the active ingredient such as sustained orprolonged release according to methods well known in the art. Liquiddosage forms for oral administration include solutions, emulsions,suspensions, syrups and elixirs.

Pharmaceutical compositions for parenteral administration includesterile aqueous and nonaqueous injectable solutions, dispersions,suspensions or emulsions as well as sterile powders to be reconstitutedin sterile injectable solutions or dispersions prior to use. Othersuitable administration forms include, but are not limited to,suppositories, sprays, ointments, creams, gels, inhalants, dermalpatches and implants.

Typical oral dosages range from about 0.001 to about 100 mg/kg bodyweight per day. Typical oral dosages also range from about 0.01 to about50 mg/kg body weight per day. Typical oral dosages further range fromabout 0.05 to about 10 mg/kg body weight per day. Oral dosages areusually administered in one or more dosages, typically, one to threedosages per day. The exact dosage will depend upon the frequency andmode of administration, the sex, age, weight and general condition ofthe subject treated, the nature and severity of the condition treatedand any concomitant diseases to be treated and other factors evident tothose skilled in the art.

The formulations may also be presented in a unit dosage form by methodsknown to those skilled in the art. For illustrative purposes, a typicalunit dosage form for oral administration may contain from about 0.01 toabout 1000 mg, from about 0.05 to about 500 mg, or from about 0.5 mg toabout 200 mg.

For parenteral routes such as intravenous, intrathecal, intramuscularand similar administration, typical doses are in the order of half thedose employed for oral administration.

The present invention also provides a process for making apharmaceutical composition comprising mixing a therapeutically effectiveamount of a compound of formula (I) and at least one pharmaceuticallyacceptable carrier or diluent. In an embodiment, of the presentinvention, the compound utilized in the aforementioned process is one ofthe specific compounds disclosed in the Experimental Section herein.

The compounds of this invention are generally utilized as the freesubstance or as a pharmaceutically acceptable salt thereof. One exampleis an acid addition salt of a compound having the utility of a freebase. When a compound of formula (I) contains a free base such salts areprepared in a conventional manner by treating a solution or suspensionof a free base of formula (I) with a molar equivalent of apharmaceutically acceptable acid. Representative examples of suitableorganic and inorganic acids are described above.

For parenteral administration, solutions of the compounds of formula (I)in sterile aqueous solution, aqueous propylene glycol, aqueous vitamin Eor sesame or peanut oil may be employed. Such aqueous solutions shouldbe suitably buffered if necessary and the liquid diluent first renderedisotonic with sufficient saline or glucose. The aqueous solutions areparticularly suitable for intravenous, intramuscular, subcutaneous andintraperitoneal administration. The compounds of formula (I) may bereadily incorporated into known sterile aqueous media using standardtechniques known to those skilled in the art.

Suitable pharmaceutical carriers include inert solid diluents orfillers, sterile aqueous solutions and various organic solvents.Examples of solid carriers include lactose, terra alba, sucrose,cyclodextrin, talc, gelatin, agar, pectin, acacia, magnesium stearate,stearic acid and lower alkyl ethers of cellulose. Examples of liquidcarriers include, but are not limited to, syrup, peanut oil, olive oil,phospholipids, fatty acids, fatty acid amines, polyoxyethylene andwater. Similarly, the carrier or diluent may include any sustainedrelease material known in the art, such as glyceryl monostearate orglyceryl distearate, alone or mixed with a wax. The pharmaceuticalcompositions formed by combining the compounds of formula (I) and apharmaceutically acceptable carrier are then readily administered in avariety of dosage forms suitable for the disclosed routes ofadministration. The formulations may conveniently be presented in unitdosage form by methods known in the art of pharmacy.

Formulations of the present invention suitable for oral administrationmay be presented as discrete units such as capsules or tablets, eachcontaining a predetermined amount of the active ingredient, andoptionally a suitable excipient. Furthermore, the orally availableformulations may be in the form of a powder or granules, a solution orsuspension in an aqueous or non-aqueous liquid, or an oil-in-water orwater-in-oil liquid emulsion.

If a solid carrier is used for oral administration, the preparation maybe tabletted, placed in a hard gelatin capsule in powder or pellet formor it may be in the form of a troche or lozenge. The amount of solidcarrier will vary widely but will range from about 25 mg to about 1 gper dosage unit. If a liquid carrier is used, the preparation may be inthe form of a syrup, emulsion, soft gelatin capsule or sterileinjectable liquid such as an aqueous or non-aqueous liquid suspension orsolution.

The pharmaceutical compositions of the invention may be prepared byconventional methods in the art. For example, tablets may be prepared bymixing the active ingredient with ordinary adjuvants and/or diluents andsubsequently compressing the mixture in a conventional tableting machineprepare tablets. Examples of adjuvants or diluents comprise: cornstarch, potato starch, talcum, magnesium stearate, gelatin, lactose,gums, and the like. Any other adjuvants or additives usually used forsuch purposes such as colorings, flavorings, preservatives etc. may beused provided that they are compatible with the active ingredients.

Treatment of Disorders

As mentioned above, the compounds of formula (I) are PDE1 enzymeinhibitors and as such are useful to treat associated neurological andpsychiatric disorders.

The invention thus provides a compound of formula (I) or apharmaceutically acceptable acid addition salt thereof, as well as apharmaceutical composition containing such a compound, for use in thetreatment of a neurodegenerative disorder, psychiatric disorder or drugaddiction in mammals including humans; wherein the neurodegenerativedisorder is selected from the group consisting of Alzheimer's disease,multi-infarct dementia, alcoholic dementia or other drug-relateddementia, dementia associated with intracranial tumors or cerebraltrauma, dementia associated with Huntington's disease or Parkinson'sdisease, or AIDS-related dementia; delirium; amnestic disorder;post-traumatic stress disorder; mental retardation; a learning disorder,for example reading disorder, mathematics disorder, or a disorder ofwritten expression; attention-deficit/hyperactivity disorder; andage-related cognitive decline; and wherein the psychiatric disorder isselected from the group consisting of schizophrenia, for example of theparanoid, disorganized, catatonic, undifferentiated, or residual type;schizophreniform disorder; schizoaffective disorder, for example of thedelusional type or the depressive type; delusional disorder;substance-induced psychotic disorder, for example psychosis induced byalcohol, amphetamine, cannabis, cocaine, hallucinogens, inhalants,opioids, or phencyclidine; personality disorder of the paranoid type;and personality disorder of the schizoid type; and wherein the drugaddiction is an alcohol, amphetamine, cocaine, or opiate addiction.

The compounds of formula (I) or pharmaceutically acceptable saltsthereof may be used as the sole active ingredient or in combination withone or more other drugs in the treatment of diseases or conditions forwhich the compounds of the present invention have utility, where thecombination of the drugs together are safer or more effective thaneither drug alone. Additionally, the compounds of the present inventionmay be used in combination with one or more other drugs that treat,prevent, control, ameliorate, or reduce the risk of side effects ortoxicity of the compounds of the present invention. Such other drugs maybe administered, by a route and in an amount commonly used therefore,contemporaneously or sequentially with the compounds of the presentinvention. Accordingly, the pharmaceutical compositions of the presentinvention include those that contain one or more other activeingredients, in addition to the compounds of the present invention. Thecombinations may be administered as part of a unit dosage formcombination product, or as a kit or treatment protocol wherein one ormore additional drugs are administered in separate dosage forms as partof a treatment regimen.

The present invention provides a method of treating a mammal, includinga human, suffering from a neurodegenerative disorder selected from acognition disorder or movement disorder, which method comprisesadministering to the subject a therapeutically effective amount of acompound of formula (I).

This invention further provides a method of treating a neurodegenerativedisorder or condition in a mammal, including a human, which methodcomprises administering to said mammal an amount of a compound offormula (I) effective in inhibiting PDE1.

This invention also provides a method of treating a subject sufferingfrom a psychiatric disorder, which method comprises administering to thesubject a therapeutically effective amount of a compound of formula (I).Examples of psychiatric disorders that can be treated according to thepresent invention include, but are not limited to, Attention DeficitHyperactivity Disorder (ADHD) schizophrenia, for example of theparanoid, disorganized, catatonic, undifferentiated, or residual type;schizophreniform disorder; schizoaffective disorder, for example of thedelusional type or the depressive type; delusional disorder;substance-induced psychotic disorder, for example psychosis induced byalcohol, amphetamine, cannabis, cocaine, hallucinogens, inhalants,opioids, or phencyclidine; personality disorder of the paranoid type;and personality disorder of the schizoid type; and the anxiety disorderis selected from panic disorder; agoraphobia; a specific phobia; socialphobia; obsessive-compulsive disorder; post-traumatic stress disorder;acute stress disorder; and generalized anxiety disorder.

It has been found that the compounds of formula (I) or pharmaceuticallyacceptable salts thereof may advantageously be administered incombination with at least one neuroleptic agent (which may be a typicalor an atypical antipsychotic agent) to provide improved treatment ofpsychiatric disorders such as schizophrenia. The combinations, uses andmethods of treatment of the invention may also provide advantages intreatment of patients who fail to respond adequately or who areresistant to other known treatments.

The present invention thus provides a method of treating a mammalsuffering from a psychiatric disorder, such as schizophrenia, whichmethod comprises administering to the mammal a therapeutically effectiveamount of a compound of formula (I), either alone or as combinationtherapy together with at least one neuroleptic agent.

The term “neuroleptic agent” as used herein refers to drugs, which havethe effect on cognition and behaviour of antipsychotic agent drugs thatreduce confusion, delusions, hallucinations, and psychomotor agitationin patients with psychoses. Also known as major tranquilizers andantipsychotic drugs, neuroleptic agents include, but are not limited to:typical antipsychotic drugs, including phenothiazines, further dividedinto the aliphatics, piperidines, and piperazines, thioxanthenes (e.g.,cisordinol), butyrophenones (e.g., haloperidol), dibenzoxazepines (e.g.,loxapine), dihydroindolones (e.g., molindone), diphenylbutylpiperidines(e.g., pimozide), and atypical antipsychotic drugs, includingbenzisoxazoles (e.g., risperidone), sertindole, olanzapine, quetiapine,osanetant and ziprasidone.

Particularly preferred neuroleptic agents for use in the invention aresertindole, olanzapine, risperidone, quetiapine, aripiprazole,haloperidol, clozapine, ziprasidone and osanetant.

The present invention further provides a method of treating a subjectsuffering from a cognition disorder, which method comprisesadministering to the subject a therapeutically effective amount of acompound of formula (I). Examples of cognition disorders that can betreated according to the present invention include, but are not limitedto, Alzheimer's disease, multi-infarct dementia, alcoholic dementia orother drug-related dementia, dementia associated with intracranialtumors or cerebral trauma, dementia associated with Huntington's diseaseor Parkinson's disease, or AIDS-related dementia; delirium; amnesticdisorder; post-traumatic stress disorder; mental retardation; a learningdisorder, for example reading disorder, mathematics disorder, or adisorder of written expression; attention-deficit/hyperactivitydisorder; and age-related cognitive decline.

This invention also provides a method of treating a movement disorder,which method comprises administering to the subject a therapeuticallyeffective amount of a compound of formula (I). Examples of movementdisorders that can be treated according to the present inventioninclude, but are not limited to, Huntington's disease and dyskinesiaassociated with dopamine agonist therapy. This invention furtherprovides a method of treating a movement disorder selected fromParkinson's disease and restless leg syndrome, which comprisesadministering to the subject a therapeutically effective amount of acompound of formula (I).

This invention also provides a method of treating a mood disorder, whichmethod comprises administering to the subject a therapeuticallyeffective amount of a compound of formula (I). Examples of mooddisorders and mood episodes that can be treated according to the presentinvention include, but are not limited to, major depressive episode ofthe mild, moderate or severe type, a manic or mixed mood episode, ahypomanic mood episode; a depressive episode with a typical features; adepressive episode with melancholic features; a depressive episode withcatatonic features; a mood episode with postpartum onset; post-strokedepression; major depressive disorder; dysthymic disorder; minordepressive disorder; premenstrual dysphoric disorder; post-psychoticdepressive disorder of schizophrenia; a major depressive disordersuperimposed on a psychotic disorder such as delusional disorder orschizophrenia; a bipolar disorder, for example bipolar I disorder,bipolar II disorder, and cyclothymic disorder. It is understood that amood disorder is a psychiatric disorder.

This invention further provides a method of treating a disordercomprising as a symptom a deficiency in attention and/or cognition in amammal, including a human, which method comprises administering to saidmammal an amount of a compound of formula (I) effective in treating saiddisorder.

Other disorders that can be treated according to the present inventionare obsessive/compulsive disorders, Tourette's syndrome and other ticdisorders.

As used herein, and unless otherwise indicated, a “neurodegenerativedisorder or condition” refers to a disorder or condition that is causedby the dysfunction and/or death of neurons in the central nervoussystem. The treatment of these disorders and conditions can befacilitated by administration of an agent which prevents the dysfunctionor death of neurons at risk in these disorders or conditions and/orenhances the function of damaged or healthy neurons in such a way as tocompensate for the loss of function caused by the dysfunction or deathof at-risk neurons. The term “neurotrophic agent” as used herein refersto a substance or agent that has some or all of these properties.

Examples of neurodegenerative disorders and conditions that can betreated according to the present invention include, but are not limitedto, Parkinson's disease; Huntington's disease; dementia, for exampleAlzheimer's disease, multi-infarct dementia, AIDS-related dementia, andFronto temperal Dementia; neurodegeneration associated with cerebraltrauma; neurodegeneration associated with stroke, neurodegenerationassociated with cerebral infarct; hypoglycemia-inducedneurodegeneration; neurodegeneration associated with epileptic seizure;neurodegeneration associated with neurotoxin poisoning; and multi-systematrophy.

In one embodiment of the present invention, the neurodegenerativedisorder or condition involves neurodegeneration of striatal mediumspiny neurons in a mammal, including a human.

In a further embodiment of the present invention, the neurodegenerativedisorder or condition is Huntington's disease.

All references, including publications, patent applications and patents,cited herein are hereby incorporated by reference in their entirety andto the same extent as if each reference were individually andspecifically indicated to be incorporated by reference and were setforth in its entirety (to the maximum extent permitted by law).

Headings and sub-headings are used herein for convenience only, andshould not be construed as limiting the invention in any way.

The use of any and all examples, or exemplary language (including “forinstance”, “for example”, “e.g.”, and “as such”) in the presentspecification is intended merely to better illuminate the invention, anddoes not pose a limitation on the scope of invention unless otherwiseindicated.

The citation and incorporation of patent documents herein is done forconvenience only, and does not reflect any view of the validity,patentability and/or enforceability of such patent documents.

The present invention includes all modifications and equivalents of thesubject-matter recited in the claims appended hereto, as permitted byapplicable law.

Compounds of the Invention

TABLE 1 Compounds of the invention PDE1A PDE1B PDE1C Compound numberCompound name IC50 (nM) IC50 (nM) IC50 (nM) 1 8-fluoro-7-methoxy-N-(3-50 9.9 28 Stereoisomer 1 methyltetrahydrofuran-3- yl)quinazolin-4-amine1 8-fluoro-7-methoxy-N-(3- 250 65 260 Stereoisomer 2methyltetrahydrofuran-3- yl)quinazolin-4-amine 2 8-fluoro-7-methoxy-N-1100 300 1300 Stereoisomer 1 methyl-N- (tetrahydrofuran-3-yl)quinazolin-4-amine 2 8-fluoro-7-methoxy-N- 100 18 76 Stereoisomer 2methyl-N- (tetrahydrofuran-3- yl)quinazolin-4-amine 38-fluoro-7-methoxy-N-(2- 1900 650 1800 Stereoisomer 1methyltetrahydrofuran-3- yl)quinazolin-4-amine 38-fluoro-7-methoxy-N-(2- 420 87 260 Stereoisomer 2methyltetrahydrofuran-3- yl)quinazolin-4-amine 38-fluoro-7-methoxy-N-(2- 530 70 310 Stereoisomer 3methyltetrahydrofuran-3- yl)quinazolin-4-amine 38-fluoro-7-methoxy-N-(2- 600 120 410 Stereoisomer 4methyltetrahydrofuran-3- yl)quinazolin-4-amine 4 8-chloro-7-methoxy-N-790 310 200 Stereoisomer 1 (tetrahydrofuran-3- yl)quinazolin-4-amine 48-chloro-7-methoxy-N- 190 45 33 Stereoisomer 2 (tetrahydrofuran-3-yl)quinazolin-4-amine 5 8-chloro-7-methoxy-N-(2- 300 49 27 stereoisomer1 methyltetrahydrofuran-3- yl)quinazolin-4-amine 58-chloro-7-methoxy-N-(2- 230 37 35 stereoisomer 2methyltetrahydrofuran-3- yl)quinazolin-4-amine 58-chloro-7-methoxy-N-(2- 1500 460 250 stereoisomer 3methyltetrahydrofuran-3- yl)quinazolin-4-amine 58-chloro-7-methoxy-N-(2- 450 58 36 stereoisomer 4methyltetrahydrofuran-3- yl)quinazolin-4-amine 6 8-chloro-7-methoxy-N-1800 330 140 stereoisomer 1 methyl-N- (tetrahydrofuran-3-yl)quinazolin-4-amine 6 8-chloro-7-methoxy-N- 150 15 11 stereoisomer 2methyl-N- (tetrahydrofuran-3- yl)quinazolin-4-amine 78-chloro-7-methoxy-N-(3- 490 75 48 stereoisomer 2methyltetrahydrofuran-3- yl)quinazolin-4-amine 78-chloro-7-methoxy-N-(3- 200 23 11 stereoisomer 1methyltetrahydrofuran-3- yl)quinazolin-4-amine 8 cis-4-(8-fluoro-7- 7221 60 Stereoisomer 1 methoxyquinazolin-4- yl)hexahydro-2H-furo[3,2-b]pyrrole 8 Stereoisomer 2 cis-4-(8-fluoro-7- 4034 2200 2500methoxyquinazolin-4- yl)hexahydro-2H-furo[3,2- b]pyrrole 9 Stereoisomer1 cis-4-(8-chloro-7- 156 40 23 methoxyquinazolin-4-yl)hexahydro-2H-furo[3,2- b]pyrrole 9 Stereoisomer 2 cis-4-(8-chloro-7-2260 1200 550 methoxyquinazolin-4- yl)hexahydro-2H-furo[3,2- b]pyrrole10 Stereoisomer 1 cis-4-(8-bromo-7- 147 49 11 methoxyquinazolin-4-yl)hexahydro-2H-furo[3,2- b]pyrrole 10 Stereoisomer 2 cis-4-(8-bromo-7-10% 47% 210 methoxyquinazolin-4- yl)hexahydro-2H-furo[3,2- b]pyrrole 11Stereoisomer 1 8-chloro-7-methoxy-N- 292 65 33 methyl-N-(3-methyltetrahydrofuran-3- yl)quinazolin-4-amine 11 Stereoisomer 28-chloro-7-methoxy-N- 152 31 15 methyl-N-(3- methyltetrahydrofuran-3-yl)quinazolin-4-amine 12 Stereoisomer 1 8-chloro-N-(2,3- 853 200 130dimethyltetrahydrofuran- 3-yl)-7- methoxyquinazolin-4- amine 12Stereoisomer 2 8-chloro-N-(2,3- 286 65 38 dimethyltetrahydrofuran-3-yl)-7- methoxyquinazolin-4- amine 12 Stereoisomer 3 8-chloro-N-(2,3-145 21 14 dimethyltetrahydrofuran- 3-yl)-7- methoxyquinazolin-4- amine12 Stereoisomer 4 8-chloro-N-(2,3- 76 7 4 dimethyltetrahydrofuran-3-yl)-7- methoxyquinazolin-4- amine 13 Stereoisomer 1 8-chloro-N-(2,3-2550 410 200 dimethyltetrahydrofuran- 3-yl)-7-methoxy-N-methylquinazolin-4-amine 13 Stereoisomer 2 8-chloro-N-(2,3- 207 34 17dimethyltetrahydrofuran- 3-yl)-7-methoxy-N- methylquinazolin-4-amine 13Stereoisomer 3 8-chloro-N-(2,3- 85 7 5 dimethyltetrahydrofuran-3-yl)-7-methoxy-N- methylquinazolin-4-amine 13 Stereoisomer 48-chloro-N-(2,3- 300 26 13 dimethyltetrahydrofuran- 3-yl)-7-methoxy-N-methylquinazolin-4-amine 14 Stereoisomer 1 8-chloro-7-methoxy-N- 2642510 200 methyl-N-(2- methyltetrahydrofuran-3- yl)quinazolin-4-amine 14Stereoisomer 2 8-chloro-7-methoxy-N- 170 18 10 methyl-N-(2-methyltetrahydrofuran-3- yl)quinazolin-4-amine 14 Stereoisomer 38-chloro-7-methoxy-N- 1532 490 200 methyl-N-(2- methyltetrahydrofuran-3-yl)quinazolin-4-amine 14 Stereoisomer 4 8-chloro-7-methoxy-N- 285 30 14methyl-N-(2- methyltetrahydrofuran-3- yl)quinazolin-4-amine 15Stereoisomer 1 8-fluoro-7-methoxy-N- 688 110 320 methyl-N-(3-methyltetrahydrofuran-3- yl)quinazolin-4-amine 15 Stereoisomer 28-fluoro-7-methoxy-N- 333 47 81 methyl-N-(3- methyltetrahydrofuran-3-yl)quinazolin-4-amine 16 Stereoisomer 1 8-fluoro-7-methoxy-N- 1180 4301200 (tetrahydrofuran-3- yl)quinazolin-4-amine 16 Stereoisomer 28-fluoro-7-methoxy-N- 315 81 230 (tetrahydrofuran-3-yl)quinazolin-4-amine 17 Stereoisomer 3 N-(2,3- 451 100 390dimethyltetrahydrofuran- 3-yl)-8-fluoro-7- methoxyquinazolin-4- amine 17Stereoisomer 2 N-(2,3- 73 5 22 dimethyltetrahydrofuran-3-yl)-8-fluoro-7- methoxyquinazolin-4- amine 17 Stereoisomer 4 N-(2,3-408 140 440 dimethyltetrahydrofuran- 3-yl)-8-fluoro-7-methoxyquinazolin-4- amine 17 Stereoisomer 1 N-(2,3- 184 27 98dimethyltetrahydrofuran- 3-yl)-8-fluoro-7- methoxyquinazolin-4- amine 18Stereoisomer 2 8-fluoro-7-methoxy-N- 2467 550 1400 methyl-N-(2-methyltetrahydrofuran-3- yl)quinazolin-4-amine 18 Stereoisomer 18-fluoro-7-methoxy-N- 1732 510 1100 methyl-N-(2-methyltetrahydrofuran-3- yl)quinazolin-4-amine 18 Stereoisomer 38-fluoro-7-methoxy-N- 200 47 87 methyl-N-(2- methyltetrahydrofuran-3-yl)quinazolin-4-amine 18 Stereoisomer 4 8-fluoro-7-methoxy-N- 515 60 120methyl-N-(2- methyltetrahydrofuran-3- yl)quinazolin-4-amine 19Stereoisomer 1 N-(2,3- 229 32 86 dimethyltetrahydrofuran-3-yl)-8-fluoro-7-methoxy- N-methylquinazolin-4- amine 19 Stereoisomer 2N-(2,3- 185 32 55 dimethyltetrahydrofuran- 3-yl)-8-fluoro-7-methoxy-N-methylquinazolin-4- amine 19 Stereoisomer 3 N-(2,3- 2487 420 1200dimethyltetrahydrofuran- 3-yl)-8-fluoro-7-methoxy- N-methylquinazolin-4-amine 19 Stereoisomer 4 N-(2,3- 97 10 34 dimethyltetrahydrofuran-3-yl)-8-fluoro-7-methoxy- N-methylquinazolin-4- amine

Experimental Section

Preparation of the Compounds of the Invention

Compounds of the general formula I of the invention may be prepared asdescribed in the following reaction schemes. Unless otherwise indicated,in the reaction schemes and discussion that follow, R₁-R₁₀, and X are asdefined above. Scheme 1 below depicts a coupling reaction between acompound of formula II and a derivative of 3-amino tetrahydrofurane offormula III, to generate the substituted halogenatedquinazolin-THF-amine compounds of formula I.

L is a leaving group, e.g. Cl, Br, I, methanesulfonyl,4-toluenesulfonyl. This reaction is typically carried out in a solventsuch as, for example, toluene, optionally in the presence of a carbonatebase, at a temperature range of from about 0° C. to about 200° C. Othersuitable solvents include benzene, chloroform, dioxane, ethyl acetate,2-propanol and xylene. Alternatively, solvent mixtures such astoluene/2-propanol can be used. Preferably the reactants are heatedunder reflux in DMSO or DMF for a period of from about 2 hours to about24 hours, optionally using a microwave oven.

The reaction depicted in Scheme 1 can also conveniently be carried outin a palladium-catalyzed fashion. Typically, a mixture of a compound offormula II, a compound of formula III and a palladium (II) source suchas Pd(OAc)₂ or Pd₂(dba)₃ is heated in a convenient solvent such astoluene in the presence of a bisphosphine ligand, such as2,2′-bis(diphenylphosphino)-1,1′-binaphthyl “BINAP”, and an al koxidebase such as sodium tert-butoxide. The reaction mixture is stirred at100° C. for 7 hr, followed by purification of the product by preparativeHPLC to obtain the desired product.

Starting materials of formula II i.e. quinazolines are eithercommercially available or can be prepared as described in the literaturee.g. Dechantsreiter, Michael A. et al From PCT Int. Appl., 2013192345,27 Dec. 2013, Armarego, Wilfred L. F. and Reece, Phillip A. AustralianJournal of Chemistry, 34(7), 1561-6; 1981, or as described in thispatent application.

Starting materials of formula III are either commercially available orcan be prepared by methods analogues to those described in theliterature e.g. Wipf, Peter; Manojlovic, Marija D. Beilstein Journal ofOrganic Chemistry (2011), 7, 824-830, Yoshimitsu, Y. et al. Journal ofOrganic Chemistry (2010), 75(11), 3843-3846, Shiau, T. P. et al.Bioorganic & Medicinal Chemistry Letters (2009), 19(4), 1110-1114.

Compounds of formula I, wherein R2 is not hydrogen, can be prepared bythe alkylation of a compounds of formula IV, wherein R2 is hydrogen,with an alkyl halide of formula V as shown in scheme 2.

This reaction is typically carried out in a suitable solvent, such asdimethyl-formamide, dimethylacetamide, tetrahydrofuran or acetonitrile,in the presence of a suitable base such as a carbonate base, e.g.potassium carbonate, or a tertiary amine base, e.g. triethylamine ordiisopropylethylamine, or a strong base such as sodium hydride at atemperature ranging from about 0° C. to about 100° C.

The invention disclosed herein is further illustrated by the followingnon-limiting examples.

General Methods

Analytical LC-MS data were obtained using the methods identified below.

Method 1: An Agilent 1200 LCMS system with ELS detector was used.Column: Agilent TC-C18 5 μm; 2.1×50 mm; Column temperature: 50° C.;Solvent system: A=water/trifluoroacetic acid (99.9:0.1) andB=acetonitrile/trifluoroacetic acid (99.95:0.05); Method: Lineargradient elution with A:B=99:1 to 0:100 in 4.0 minutes and with a flowrate of 0.8 mL/minute.

Method 2: An Agilent 1200 LCMS system with ELS detector was used.Column: XBridge ShieldRP18, 5 μm, 50×2.1 mm; Column temperature: 40° C.;Solvent system: A=water/NH₃*H2O (99.95:0.05) and B=acetonitrile; Method:Linear gradient elution with A:B=95:5 to 0:100 in 3.4 minutes and with aflow rate of 0.8 mL/minute.

Method 3: An Agilent 1200 LCMS system with ELS detector was used.Column: XBridge ShieldRP18, 5 μm, 50×2.1 mm; Column temperature: 40° C.;Solvent system: A=water/NH₃*H2O (99.95:0.05) and B=acetonitrile; Method:Linear gradient elution with A:B=99:1 to 0:100 in 3.4 minutes and with aflow rate of 0.8 mL/minute.

Method 4: An Agilent 1100 LCMS system with ELS detector was used.Column: YMC ODS-AQ, 5 μm, 50×2.0 mm; Column temperature: 50° C.; Solventsystem: A=0.1% TFA in water and B=0.05% TFA in Acetonitrile; Method:Linear gradient elution with A:B=99:1 to 5:95 in 3.5 minutes and with aflow rate of 0.8 mL/minute.

Method 5: An Agilent 1200 LCMS system with ELS detector was used.Column: Agilent TC-C18 5 μm; 2.1×50 mm; Column temperature: 50° C.;Solvent system: A=water/trifluoroacetic acid (99.9:0.1) andB=acetonitrile/trifluoroacetic acid (99.95:0.05); Method: Lineargradient elution with A:B=90:10 to 0:100 in 4.0 minutes and with a flowrate of 0.8 mL/min.

Preparative LC-MS-purification was performed on a PE Sciex API 150EXinstrument with atmospheric pressure chemical ionization. Column: 50×20mm YMC ODS-A with 5 μm particle size; Solvent system:A=water/trifluoroacetic acid (99.965:0.035) andB=acetonitrile/water/trifluoroacetic acid (94.965:5:0.035); Method:Linear gradient elution with A:B=80:20 to 0:100 in 7 minutes and with aflow rate of 22.7 mL/minute. Fraction collection was performed bysplit-flow MS detection.

Preparative SFC was performed on a Thar 80 instrument. Exemplifiedconditions can be, but not limited to: Column AD 250×30 mm with 20 μmparticle size; Column temperature: 38° C., Mobile phase: SupercriticalCO₂/EtOH(0.2% NH₃H₂O)=45/55.

Synthesis of Intermediate I:

4-Chloro-8-fluoro-7-methoxyquinazoline:

Step 1: Commercial available (CAS 1180497-45-3)2-amino-3-fluoro-4-methoxybenzoic acid (8 g, 43.21 mmol) and ammoniumacetate (67 g, 864 mol) in trimethoxymethane (250 mL) were stirred at100° C. for 12 hrs. The mixture was filtered and washed with water (3×20mL), the white solid was dried under vacuum to give8-fluoro-7-methoxyquinazolin-4(3H)-one (8 g, 95%).

Step 2: To a mixture of 8-fluoro-7-methoxyquinazolin-4(3H)-one (4.0 g,20.6 mmol) and diisopropylethylamine (11 g, 82 mmol) in toluene (100 mL)was added POCl₃ (6.32 g, 41.2 mmol) at 0° C. The reaction was stirred at100° C. for 12 hrs. The mixture was then cooled to 20° C. and pouredinto ice-water (100 mL). The water phase was extracted withdichloromethane (3×100 mL). The combined organic phases were washed withbrine (3×10 mL) and concentrated under vacuum. The residue was purifiedby flash chromatography on silica gel using a gradient of ethyl acetateand petroleum ether to give 4-chloro-8-fluoro-7-methoxyquinazoline 3 g(70%).

Example 1:

8-Fluoro-7-methoxy-N-(3-methyltetrahydrofuran-3-yl)quinazolin-4-amine:

A mixture of 4-chloro-8-fluoro-7-methoxyquinazoline (560 mg, 2.63 mmol),(+/−)-3-methyltetrahydrofuran-3-amine hydrochloride (400 mg, 2.92 mmol)and K₂CO₃ (800 mg, 5.84 mmol) in DMSO (30 mL) was stirred at 100° C. for12 hours. The solution was then poured into ice-water (100 mL) andextracted with dichloromethane (3×50 mL). The combined organic phaseswere washed with brine (3×10 mL), dried over MgSO₄ and concentratedunder vacuum. The residue was purified by flash chromatography on silicagel using a gradient of ethyl acetate and petroleum ether to give(+/−)-8-fluoro-7-methoxy-N-(3-methyltetrahydrofuran-3-yl)quinazolin-4-amine320 mg (44%).

The racemic mixture (320 mg) was purified by SFC (Column: AY (250 mm*30mm,5 um)) separation and numbered according to the order of elution:

Stereoisomer 1 (First Eluting by SFC): 140 mg

¹H NMR (CDCl₃, 400 MHz): δ8.66 (s, 1H), 7.44 (d, J=8.8 Hz, 1H), 7.19 (t,J=8.4 Hz, 1H), 5.68 (s, 1H), 4.16 (d, J=9.2 Hz, 1H), 4.05 (s, 3H),4.02-3.98 (m, 2H), 3.87 (d, J=9.2 Hz, 1H), 2.66-2.60 (m, 1H), 2.17-2.09(m, 1H), 1.75 (s, 3H).

LC-MS: (m/z) 278.1 (MH+) t_(R) (minutes, method 1)=1.84 minutes.

[α]²⁰ _(D)=18° (c=0.1 mg/mL, methanol).

Stereoisomer 2 (Second Eluting by SFC): 160 mg

¹H NMR (CDCl₃, 400 MHz): δ8.66 (s, 1H), 7.44 (dd, J=8.8, 1.6 Hz, 1H),7.19 (t, J=8.4 Hz, 1H), 5.70 (s, 1H), 4.16 (d, J=9.2 Hz, 1H), 4.05 (s,3H), 4.02-3.98 (m, 2H), 3.87 (d, J=9.2 Hz, 1H), 2.66-2.60 (m, 1H),2.16-2.09 (m, 1H), 1.75 (s, 3H).

LC-MS: (m/z) 278.1 (MH+) t_(R) (minutes, method 1)=1.84 minutes.

[α]²⁰ _(D)=−26° (c=0.1 mg/mL, methanol)

Example 2:

8-Fluoro-7-methoxy-N-methyl-N-(tetrahydrofuran-3-yl)quinazolin-4-amine:

Step 1: A solution of 4-chloro-8-fluoro-7-methoxyquinazoline (440 mg,2.06 mmol), tetrahydrofuran-3-amine (200 mg, 2.29 mmol) anddiisopropylethylamine (600 mg, 4.58 mmol) in DMF (30 mL) was stirred at100° C. for 12 hrs. The solution was concentrated under vacuum, and theresidue was purified by flash chromatography on silica gel using agradient of ethyl acetate and petroleum ether to give8-fluoro-7-methoxy-N-(tetrahydrofuran-3-yl)quinazolin-4-amine 500 mg(83%) as a white solid. Step 2: To a solution of8-fluoro-7-methoxy-N-(tetrahydrofuran-3-yl)quinazolin-4-amine (480 mg,1.83 mmol) in THF (20 mL) was added a 60% suspension of NaH in mineraloil (100 mg, 2.74 mmol) at 0° C., then it was stirred at 0° C. for 30min and then allowed to warm to room temperature. Methyliodide (388 mg,2.74 mmol) was added at 20° C. and the reaction was stirred at 20° C.for 12 hrs. The solution was quenched with sat. aq. NH₄Cl (2 mL), thenconcentrated under vacuum. The residue was diluted with dichloromethane(100 mL), washed with brine (3×10 mL), dried over MgSO₄ and concentratedunder vacuum. The crude product was purified by flash chromatography onsilica gel using a gradient of ethyl acetate and petroleum ether to give8-fluoro-7-methoxy-N-methyl-N-(tetrahydrofuran-3-yl)quinazolin-4-amine230 mg (46%).

The mixture of stereoisomers (230 mg) was purified by SFC (Column: AD-H(250 mm*30 mm,5 um)) separation and numbered according to the order ofelution:

Stereoisomer 1 (First Eluting by SFC): 75 mg

¹H NMR (CDCl₃, 400 MHz): δ8.66 (s, 1H), 7.77-7.74 (m, 1H), 7.19-7.15 (m,1H), 5.29-5.23 (m, 1H), 4.17-4.12 (m, 1H), 4.07 (s, 3H), 3.99 (d, J=5.6Hz, 2H), 3.75 (q, J=7.6 Hz, 1H), 3.32 (s, 3H), 2.49-2.44 (m, 1H),2.12-2.08 (m, 1H).

LC-MS: (m/z) 278.1 (MH+) t_(R) (minutes, method 1)=1.78 minutes.

[α]²⁰ _(D)=−15° (c=0.1 mg/mL, methanol)

Stereoisomer 2 (Second Eluting by SFC): 80 mg

¹H NMR (CDCl₃, 400 MHz): δ8.66 (s, 1H), 7.76 (dd, J=9.2, 2.0 Hz, 1H),7.18 (dd, J=9.2, 8.0 Hz, 1H), 5.31-5.23 (m, 1H), 4.17-4.12 (m, 1H), 4.06(s, 3H), 3.99 (d, J=5.6 Hz, 2H), 3.75 (q, J=7.6 Hz, 1H), 3.32 (s, 3H),2.48-2.44 (m, 1H), 2.12-2.08 (m, 1H).

LC-MS: (m/z) 278.1 (MH+) t_(R) (minutes, method 1)=1.79 minutes.

[α]²⁰ _(D)=16° (c=0.1 mg/mL, methanol)

Example 3

8-Fluoro-7-methoxy-N-(2-methyltetrahydrofuran-3-yl)quinazolin-4-amine:

A solution of 4-chloro-8-fluoro-7-methoxyquinazoline (500 mg, 2.35mmol), 2-methyltetrahydrofuran-3-amine hydrochloride (388 mg, 2.82 mmol)and diisopropylethylamine (607 mg, 4.70 mmol) in DMF (20 mL) was stirredat 100° C. for 12 hours. The solution was concentrated under vacuum, andthe residue was purified by flash chromatography on silica gel using agradient of ethyl acetate and petroleum ether to give a8-fluoro-7-methoxy-N-(2-methyltetrahydrofuran-3-yl)quinazolin-4-amine asa mixture of all four possible stereoisomers 600 mg (84%).

The mixture of stereoisomers (600 mg) was purified by SFC (Column: AD(250 mm*30 mm,5 um)) separation and numbered according to the order ofelution:

Stereoisomer 1 (First Eluting by SFC): 180 mg

¹H NMR (CDCl₃, 400 MHz): δ8.66 (s, 1H), 7.47 (dd, J=8.8, 1.2 Hz, 1H),7.21 (t, J=8.8 Hz, 1H), 5.72 (d, J=6.8 Hz, 1H), 4.64-4.58 (m, 1H),4.09-3.98 (m, 6H), 2.59-2.50 (m, 1H), 2.00-1.96 (m, 1H), 1.36 (d, J=6.4Hz, 3H).

LC-MS: (m/z) 278.1 (MH+) t_(R) (minutes, method 1)=1.84 minutes.

[α]²⁰ _(D)=−23° (c=0.1 mg/mL, methanol)

Stereoisomer 2 (Second Eluting by SFC): 80 mg

¹H NMR (CDCl₃, 400 MHz): δ8.65 (s, 1H), 7.48 (dd, J=9.2, 1.6 Hz, 1H),7.24-7.20 (m, 1H), 5.68 (d, J=8.4 Hz, 1H), 5.07-5.02 (m, 1H), 4.11-4.01(m, 5H), 3.85-3.82 (m, 1H), 2.56-2.50 (m, 1H), 2.03-1.99 (m, 1H), 1.26(d, J=6.0 Hz, 3H).

LC-MS: (m/z) 278.1 (MH+) t_(R) (minutes, method 1)=1.82 minutes.

[α]²⁰ _(D)=22° (c=0.1 mg/mL, methanol)

Stereoisomer 3 (Third Eluting by SFC): 180 mg

¹H NMR (CDCl₃, 400 MHz): δ8.64 (s, 1H), 7.48 (dd, J=9.2, 1.6 Hz, 1H),7.24-7.19 (m, 1H), 5.71 (d, J=8.4 Hz, 1H), 5.07-5.02 (m, 1H), 4.11-4.01(m, 5H), 3.85-3.82 (m, 1H), 2.56-2.50 (m, 1H), 2.03-1.97 (m, 1H), 1.26(d, J=6.4 Hz, 3H).

LC-MS: (m/z) 278.1 (MH+) t_(R) (minutes, method 1)=1.81 minutes.

[α]²⁰ _(D)=−21° (c=0.1 mg/mL, methanol)

Stereoisomer 4 (Fourth Eluting by SFC): 80 mg

¹H NMR (CDCl₃, 400 MHz): δ8.66 (s, 1H), 7.47 (dd, J=8.8, 1.2 Hz, 1H),7.21 (t, J=8.8 Hz, 1H), 5.72 (d, J=7.2 Hz, 1H), 4.64-4.60 (m, 1H),4.09-3.98 (m, 6H), 2.59-2.50 (m, 1H), 2.00-1.93 (m, 1H), 1.36 (d, J=6.4Hz, 3H).

LC-MS: (m/z) 278.1 (MH+) t_(R) (minutes, method 1)=1.85 minutes.

[α]²⁰ _(D)=34° (c=0.1 mg/mL, methanol)

Synthesis of Intermediate II:

4,8-dichloro-7-methoxyquinazoline

Step 1: To the suspension of commercial available (CAS 33234-36-5)2-chloro-3-methoxybenzoic acid (19.5 g, 104 mmol) in acetic acid (100mL) and H₂O (100 mL) at room temperature was added bromine (10.8 mL, 209mmol) dropwise. The resulting mixture was heated at 60° C. overnight.Then cooled to room temperature and extracted with dichloromethane(3×200 mL). The combined organic phases were washed with water (3×300mL), dried over Na₂SO₄, filtered and concentrated to give6-bromo-2-chloro-3-methoxybenzoic acid 23 g (83%).

Step 2: To as suspension of 6-bromo-2-chloro-3-methoxybenzoic acid (10g, 38 mmol) in toluene (200 mL) was added diphenylphosphoryl azide (12.2mL, 56.6 mmol) triethylamine (15.8 mL, 113 mmol) and tert-butanol (18.0ml, 188 mmol). The reaction mixture was heated at 100° C. for 2 hrsunder N₂. The mixture was evaporated and the residue was diluted withethyl acetate. The organic phase was washed with 5% aqueous citric acidsolution, water, sat. aq. NaHCO₃, brine, dried over Na₂SO₄, andconcentrated. The crude product was purified by flash chromatography onsilica gel using a gradient of ethyl acetate and petroleum ether,yielding tert-butyl (6-bromo-2-chloro-3-methoxyphenyl)carbamate 12 g(95%).

Step 3: To an ice-cold solution of tert-butyl(6-bromo-2-chloro-3-methoxyphenyl)carbamate (12 g, 37 mmol) indichloromethane (150 mL) was added trifluoroacetic acid (20 mL). Themixture was warmed to room temperature and stirred for 5 hrs. Thesolution was then concentrated and the residue was diluted withdichloromethane, adjusted to pH=9 by sat. aq. NaHCO₃, washed with water,dried over Na₂SO₄, filtered and concentrated to give6-bromo-2-chloro-3-methoxyaniline 8.3 g (98%).

Step 4: To a solution of 6-bromo-2-chloro-3-methoxyaniline (8.3 g, 35mmol) in methanol (300 mL) was added 1,3-bis(diphenylphosphino)propane(2.90 g, 7.02 mmol), Pd(AcO)₂ (1.58 g, 7.02 mmol) and triethylamine(4.89 mL, 35.1 mmol). The reaction mixture was stirred at 100° C. underan atmosphere of CO (3 MPa) for 2 days. The mixture was cooled to roomtemperature and filtered. The filtrate was concentrated and the residuewas dissolved in dichloromethane. The resulting solution was washed withwater, dried over Na₂SO₄, filtered and concentrated. The crude productwas purified by flash chromatography on silica gel using a gradient ofethyl acetate and petroleum ether to yield methyl2-amino-3-chloro-4-methoxybenzoate 5.0 g (65%).

Step 5: To a solution of methyl 2-amino-3-chloro-4-methoxybenzoate (4.95g, 23.0 mmol) in a mixture of THF (60 mL) and H₂O (30 mL) was addedLiOH·H₂O (2.89 g, 68.8 mmol). The mixture was heated at 50° C. for 3days. The mixture was then cooled to room temperature and extracted withethyl acetate. The aqueous phase was acidified by aq. KHSO₄ until pH=3,filtered, and the filter cake was collected, washed with water and driedto give 2-amino-3-chloro-4-methoxybenzoic acid 3.2 g (69%).

Step 6: To a solution of 2-amino-3-chloro-4-methoxybenzoic acid (700 mg,3.47 mmol) in CH(OMe)₃ (40 mL) was added ammonium acetate (5.35 g, 69.4mmol). The mixture was then heated at 90° C. overnight. The reaction wascooled to room temperature, filtered and the filter cake was collected,washed with water and dried to give8-chloro-7-methoxyquinazolin-4(3H)-one 630 mg (86%).

Step 7: To an ice-cold solution of8-chloro-7-methoxyquinazolin-4(3H)-one (630 mg, 2.99 mmol) in toluene(15 mL) was dropwise added POCl₃ (0.56 mL, 6.0 mmol) anddiisopropylethylamine (2.08 mL, 12.0 mmol). The mixture was heated at100° C. overnight, then cooled to room temperature and carefully pouredinto ice-water. The water phase was extracted with dichloromethane (2×30mL). The combined organic phases were washed with water, dried overNa₂SO₄, filtered, concentrated in vacuo. The crude product was purifiedby flash chromatography on silica gel using a gradient ofdichloromethane and ethyl acetate to give4,8-dichloro-7-methoxyquinazoline 580 mg (85%).

Example 4:

8-Chloro-7-methoxy-N-(tetrahydrofuran-3-yl)quinazolin-4-amine:

To a solution of 4,8-dichloro-7-methoxyquinazoline (650 mg, 2.84 mmol)in dimethylformamide (20 mL) was added tetrahydrofuran-3-amine (297 mg,3.41 to mmol) and diisopropylethylamine (0.99 mL, 5.7 mmol). Through themixture was bubbled N₂ for 5 minutes. The reaction was then heated at100° C. for 3 hrs under an atmosphere of N₂. The crude mixture wasconcentrated and the residue was purified by flash chromatography onsilica gel using a gradient of ethyl acetate and petroleum ether to give8-chloro-7-methoxy-N-(tetrahydrofuran-3-yl)quinazolin-4-amine 650 mg(82%).

The racemic mixture (650 mg) was purified by SFC (Column: Chiral Pak AD5 μm, Daicel Chemical Industries, Ltd, 250×30 mm I.D.) separation andnumbered according to the order of elution:

Stereoisomer 1 (First Eluting by SFC): 200 mg

¹H NMR (CD₃OD, 400 MHz): δ8.45 (s, 1H), 8.20 (d, J=9.29 Hz, 1H), 7.38(d, J=9.29 Hz, 1H), 3.99˜4.07 (m, 5H), 3.77˜3.89 (m, 2H), 2.32˜2.42 (m,1H), 2.04˜2.14 (m, 1H).

LC-MS: (m/z) 280.1 (MH+) t_(R) (minutes, method 2)=1.58 minutes

[α]_(D) ²⁰+38.3° (c=0.10, methanol).

Stereoisomer 2 (Second Eluting by SFC): 200 mg

¹H NMR (CD₃OD, 400 MHZ): δ8.45 (s, 1H), 8.20 (d, J=9.29 Hz, 1H), 7.38(d, J=9.05 Hz, 1H), 3.99˜4.07 (m, 5H), 3.77˜3.89 (m, 2H), 2.32˜2.42 (m,1H), 2.04˜2.14 (m, 1H).

LC-MS: (m/z) 280.1 (MH+) t_(R) (minutes, method 1)=1.57 minutes

[α]_(D) ²⁰−32.0° (c=0.10, methanol).

Example 5

8-Chloro-7-methoxy-N-(2-methyltetrahydrofuran-3-yl)quinazolin-4-amine:

To a solution of 4,8-dichloro-7-methoxyquinazoline (450 mg, 1.96 mmol)in DMF (20 mL) was added 2-methyltetrahydrofuran-3-amine (mixture of all4 stereoisomers) (322 mg, 2.36 mmol) and diisopropylethylamine (1.03 mL,5.89 mmol). Through the mixture was bubbled N₂ for 5 minutes and it wasthen heated at 100° C. overnight. The crude mixture was concentrated andthe residue was purified by flash chromatography on silica gel using agradient of ethyl acetate and petroleum ether to yield8-chloro-7-methoxy-N-(2-methyltetrahydrofuran-3-yl)quinazolin-4-amine450 mg (78%) as a mixture of all four possible stereoisomers.

A mixture of stereoisomers (750 mg) was purified by SFC separation(column: Chiral Pak AD 5 μm, Daicel Chemical Industries, Ltd) andnumbered according to the order of elution:

Stereoisomer 1 (First Eluting by SFC): 131 mg

¹H NMR (CD₃OD, 400 MHz): δ8.45 (s, 1H), 8.19 (d, J=9.6 Hz, 1H), 7.39 (d,J=9.2 Hz, 1H), 4.52˜4.57 (m, 1H), 4.04 (s, 4H), 3.97˜4.02 (m, 2H),2.41˜2.50 (m, 1H), 1.97˜2.04 (m, 1H), 1.32 (d, J=6.4 Hz, 3H).

LC-MS: (m/z) 294.1 (MH+) t_(R) (minutes, method 1)=1.93 minutes

[α]_(D) ²⁰=−59.3° (c=0.10, methanol).

Stereoisomer 2 (Second Eluting by SFC): 97 mg

¹H NMR (CD₃OD, 400 MHz): δ8.43 (s, 1H), 8.25 (d, J=9.2 Hz, 1H), 7.39 (d,J=9.6 Hz, 1H), 5.01˜5.06 (m, 1H), 4.09˜4.14 (m, 2H), 4.04 (s, 3H), 3.72(q, J=8.0 Hz, 3H), 2.40˜2.46 (m, 1H), 2.10˜2.14 (m, 1H), 1.09 (d, J=6.0Hz, 3H).

LC-MS: (m/z) 294.1 (MH+) t_(R) (minutes, method 2)=1.73 minutes

[α]_(D) ²⁰=−28.3° (c=0.10, methanol).

Stereoisomer 3 (Third Eluting by SFC): 37 mg

¹H NMR (CD₃OD varian 400): δ8.43 (s, 1H), 8.24 (d, J=9.2 Hz, 1H), 7.38(d, J=9.2 Hz, 1H), 5.00˜5.05 (m, 1H), 4.10˜4.14 (m, 2H), 4.04 (s, 3H),3.72 (q, J=8.0 Hz, 3H), 2.41˜2.46 (m, 1H), 2.09˜2.14 (m, 1H), 1.09 (d,J=6.4 Hz, 3H).

LC-MS: (m/z) 294.1 (MH+) t_(R) (minutes, method 1)=1.73 minutes

[α]_(D) ²⁰=+29.3° (c=0.10, methanol).

Stereoisomer 4 (Fourth Eluting by SFC): 50 mg

¹H NMR (H000269489 H20773-029-4A MeOD varian 400): δ8.46 (s, 1H), 8.20(d, J=9.2 Hz, 1H), 7.39 (d, J=9.2 Hz, 1H), 4.53˜4.57 (m, 1H), 4.04 (s,3H), 3.97˜4.02 (m, 3H), 2.43˜2.48 (m, 1H), 1.99˜2.04 (m, 1H), 1.32 (d,J=6.4 Hz, 3H).

LC-MS: (m/z) 294.1 (MH+) t_(R) (minutes, method 1)=1.77 minutes

[α]_(D) ²⁰=+62.7° (c=0.10, methanol).

Example 6

8-Chloro-7-methoxy-N-methyl-N-(tetrahydrofuran-3-yl)quinazolin-4-amine,stereoisomer 1:

To an ice-cold solution of stereoisomer 1 of8-chloro-7-methoxy-N-(tetrahydrofuran-3-yl)quinazolin-4-amine (150 mg,0.54 mmol) in a mixture of THF (4 mL) and dimethylformamide (2 mL) wasadded NaH (32 mg, 0.81 mmol, 60% in mineral oil). The mixture wasstirred at 0° C. for 30 minutes. Then methyliodide (100 mg, 0.70 mmol)was added at 0° C. The reaction was stirred at room temperature for 3hours and then quenched with sat. NH₄Cl (aq) (2 mL). The crude reactionmixture was concentrated and the residue purified by preparatory TLC(dichloromethane/methanol=50/1) to give8-chloro-7-methoxy-N-methyl-N-(tetrahydrofuran-3-yl)quinazolin-4-amine(stereoisomer 1).

23 mg (14%)

¹H NMR (CD₃OD, 400 MHz): δ8.49 (s, 1H), 8.11 (d, J=9.6 Hz, 1H), 7.39 (d,J=9.6 Hz, 1H), 5.24˜5.30 (m, 1H), 4.10˜4.13 (m, 1H), 4.06 (s, 3H),3.94˜3.98 (m, 2H), 3.73 (q, J=8.0 Hz, 1H), 3.34 (s, 3H), 2.45˜2.49 (m,1H), 2.13˜2.18 (m, 1H).

LC-MS: (m/z) 294.0 (MH+) t_(R) (minutes, method 3)=2.55 minutes

[α]_(D) ²⁰=19.3° (c=0.10, CHCl₃)

8-Chloro-7-methoxy-N-methyl-N-(tetrahydrofuran-3-yl)quinazolin-4-amine,stereoisomer 2

To an ice-cold solution of stereoisomer 2 of8-chloro-7-methoxy-N-(tetrahydrofuran-3-yl)quinazolin-4-amine (150 mg,0.54 mmol) in a mixture of THF (4 mL) and DMF (2 mL) was added NaH (32mg, 0.81 mmol, 60% in mineral oil). The reaction was stirred at 0° C.for 30 minutes Then CH₃I (100 mg, 0.70 mmol) was added at 0° C. Thereaction was allowed to warm to RT and stirred for 3 hours. The reactionwas quenched with sat. NH₄Cl (aq) (2 mL). Then concentrated and theresidue was purified by preparatory TLC (dichloromethane/methanol=50/1)give stereoisomer 2 of8-chloro-7-methoxy-N-methyl-N-(tetrahydrofuran-3-yl)quinazolin-4-amine.

25 mg (16%)

¹H NMR (H000271637 H20773-033-2B MeOD varian 400): δ8.49 (s, 1H), 8.11(d, J=9.6 Hz, 1H), 7.40 (d, J=9.6 Hz, 1H), 5.24˜5.31 (m, 1H), 4.10˜4.13(m, 1H), 4.06 (s, 3H), 3.94˜3.98 (m, 2H), 3.73 (q, J=7.6 Hz, 1H), 3.34(s, 3H), 2.44˜2.49 (m, 1H), 2.13˜2.18 (m, 1H).

LC-MS: (m/z) 294.0 (MH+) t_(R) (minutes, method 1)=2.11 minutes

[α]_(D) ²⁰=−7.7° (c=0.10, CHCl₃).

Example 7

8-Chloro-7-methoxy-N-(3-methyltetrahydrofuran-3-yl)quinazolin-4-amine:

To a solution of 4,8-dichloro-7-methoxyquinazoline (350 mg, 1.53 mmol)in DMSO (30 mL) was added 3-methyltetrahydrofuran-3-amine (210 mg, 1.53mmol) and NaHCO₃ (257 mg, 3.06 mmol). The mixture was heated at 100° C.for 3 hours. Then cooled to room temperature and quenched with H₂O (10mL). The resulting mixture was extracted with dichloromethane (3×20 ml).The combined organic phases were washed with H₂O (50 mL), dried overNa₂SO₄, filtered, and concentrated. The residue was purified byprep-HPLC to give8-chloro-7-methoxy-N-(3-methyltetrahydrofuran-3-yl)quinazolin-4-amine200 mg (45%).

The racemic mixture (200 mg) was purified by SFC (Column: Chiralpak AD250×30 mm I.D.,5 um) separation and numbered according to the order ofelution:

Stereoisomer 1 (First Eluting by SFC): 43 mg

¹H NMR (CD₃OD, 400 MHz): δ8.46 (s, 1H), 8.21 (d, J=9.2 Hz, 1H), 7.39 (d,J=9.6 Hz, 1H), 4.19 (d, J=9.2 Hz, 1H), 4.04 (s, 3H), 3.93˜3.99 (m, 3H),2.56˜2.62 (m, 1H), 2.13˜2.20 (m, 1H), 1.67 (s, 3H).

LC-MS: (m/z) 294.0 (MH+) t_(R) (minutes, method 4)=2.16 minutes

[α]_(D) ²⁰=+8.3° (c=0.10, CHCl₃).

Stereoisomer 2 (Second Eluting by SFC): 39 mg

¹H NMR (CD₃OD, 400): δ8.46 (s, 1H), 8.21 (d, J=9.2 Hz, 1H), 7.39 (d,J=9.2 Hz, 1H), 4.19 (d, J=9.2 Hz, 1H), 4.04 (s, 3H), 3.93˜3.99 (m, 3H),2.56˜2.62 (m, 1H), 2.13˜2.20 (m, 1H), 1.67 (s, 3H).

LC-MS: (m/z) 294.0 (MH+) t_(R) (minutes, method 4)=2.17 minutes

[α]_(D) ²⁰=−5.7° (c=0.10, CHCl₃).

Example 8

Cis-4-(8-fluoro-7-methoxyquinazolin-4-yl)hexahydro-2H-furo[3,2-b]pyrrole:

A mixture of 4-chloro-8-fluoro-7-methoxyquinazoline (320 mg, 1.50 mmol),cis-hexahydro-2H-furo[3,2-b]pyrrole (200 mg, 1.77 mmol) anddiisopropylethylamine (457 mg, 3.54 mmol) in DMF (30 mL) was stirred at100° C. for 12 hrs. The solution was concentrated in vacuo, the residuewas diluted with dichloromethane (100 mL), washed with brine (3×10 mL),dried and concentrated in vacuo. The crude product was purified by flashchromatography on silica gel using a gradient of ethyl acetate andpetroleum ether to give racemiccis-4-(8-fluoro-7-methoxyquinazolin-4-yl)hexahydro-2H-furo[3,2-b]pyrrole(300 mg, 69%).

The racemate ofcis-4-(8-fluoro-7-methoxyquinazolin-4-yl)hexahydro-2H-furo[3,2-b]pyrrole(300 mg) was purified by SFC (Column: IC (250 mm*30 mm,10 um))separation and numbered according to the order of elution:

Stereoisomer 1:

100 mg (33%)

¹H NMR (CDCl₃, 400 MHz): δ8.62 (s, 1H), 7.90 (dd, J=9.2,1.6 Hz, 1H),7.15 (t, J=8.8 Hz, 1H), 5.15 (t, J=4.9 Hz, 1H), 4.60 (d, J=4.2 Hz, 1H),4.11-4.09 (m, 2H), 4.06 (s, 3H), 3.95-3.91 (m, 2H), 2.44-2.33 (m, 2H),2.18-2.15 (m, 1H), 2.04-2.01 (m, 1H).

LC-MS (m/z) 290.1 (MH⁺) t_(R) (minutes, method 1)=1.81

[α]_(D) ²⁰+181.3° (c=0.10, methanol).

Stereoisomer 2:

100 mg (33%)

¹H NMR (CDCl₃, 400 MHz): δ8.63 (s, 1H), 7.91 (dd, J=9.2, 1.6 Hz, 1H),7.15 (t, J=8.8 Hz, 1H), 5.15 (t, J=4.8 Hz, 1H), 4.60 (t, J=4.4 Hz, 1H),4.12-4.09 (m, 2H), 4.06 (s, 3H), 3.95-3.91 (m, 2H), 2.44-2.33 (m, 2H),2.18-2.15 (m, 1H), 2.04-2.01 (m, 1H).

LC-MS (m/z) 290.1 (MH⁺) t_(R) (minutes, method 1)=1.80.

[α]_(D) ²⁰−202° (c=0.10, methanol).

Example 9

Cis-4-(8-chloro-7-methoxyquinazolin-4-yl)hexahydro-2H-furo[3,2-b]pyrrole:

To a solution of 4,8-dichloro-7-methoxyquinazoline (350 mg, 1.53 mmol)in DMF (12 mL) was added hexahydro-2H-furo[3,2-b]pyrrole (208 mg, 1.84mmol) and diisopropylethylamine (0.54 mL, 3.0 mmol). Nitrogen wasbubbled through the mixture for 2 min and it was heated at 100° C.overnight. The reaction was concentrated in vacuo, suspended in ethylacetate and stirred for 1 hr at room temperature. The solid was filteredoff and washed with ethyl acetate to give4-(8-chloro-7-methoxyquinazolin-4-yl)hexahydro-2H-furo[3,2-b]pyrrole(400 mg, 99%). The racemate of4-(8-chloro-7-methoxyquinazolin-4-yl)hexahydro-2H-furo[3,2-b]pyrrole(400 mg) was purified by SFC (Column: Chiral Cel OJ 20 μm, DaicelChemical Industries, Ltd 250×30 mm I.D) separation and numberedaccording to the order of elution:

Stereoisomer 1

106 mg, (26.5%)

¹H NMR (CD₃OD, 400 MHz): δ8.47 (s, 1H), 8.31 (d, J=9.2 Hz, 1H), 7.40 (d,J=9.6 Hz, 1H), 5.20 (t, J=4.8 Hz, 1H), 4.61 (t, J=4.0 Hz, 1H), 4.14˜4.18(m, 2H), 4.08 (s, 3H), 3.92˜3.95 (m, 2H), 2.43˜2.48 (m, 1H), 2.29˜2.32(m, 1H), 2.07˜2.13 (m, 1H).

LC-MS (m/z) 306.1 (MH⁺) t_(R) (minutes, method 1)=1.88

[α]_(D) ²⁰+280° (c=0.10, methanol).

Stereoisomer 2:

102 mg (25.5%)

¹H NMR (CD₃OD, 400 MHz): δ8.44 (s, 1H), 8.28 (d, J=9.6 Hz, 1H), 7.37 (d,J=9.6 Hz, 1H), 5.17 (t, J=4.8 Hz, 1H), 4.59 (t, J=4.0 Hz, 1H), 4.09˜4.15(m, 2H), 4.05 (s, 3H), 3.87˜3.94 (m, 2H), 2.37˜2.48 (m, 1H), 2.24˜2.32(m, 1H), 1.99˜2.15 (m, 1H).

LC-MS (m/z) 306.1 (MH⁺) t_(R) (minutes, method 1)=1.89

[α]_(D) ²⁰−301° (c=0.10, methanol).

Intermediate III

8-Bromo-4-chloro-7-methoxyquinazoline:

Step 1: To a suspension of 2-amino-3-bromo-4-methoxybenzoic acid(CAS1180497-47-5) (5.50 g, 22.4 mmol) in trimethoxymethane (100 mL) wasadded NH₄OAc (17.2 g, 224 mmol). The mixture was heated at 90° C. for 12hrs. The mixture was cooled to 25° C., the solid was filtered off,washed with H₂O (50 mL) and dried in vacuo to give8-bromo-7-methoxyquinazolin-4(3H)-one 3.50 g (61.4%).

Step 2: To an ice-cold solution of 8-bromo-7-methoxyquinazolin-4(3H)-one(3.50 g, 13.7 mmol) in dry toluene (50 mL) was addeddiisopropylethylamine (7.09 g, 54.9 mmol) and POCl₃ (18 g, 0.12 mol)dropwise. The mixture was heated at 100° C. for 12 hrs, then cooled to25° C. and poured into H₂O (100 mL). The aqueous layer was extractedwith dichloromethane (100 mL). The organic layer was dried over Na₂SO₄,filtered and concentrated in vacuo. The crude product was purified byflash chromatography on silica gel using a gradient of dichloromethaneand ethyl acetate to give 8-bromo-4-chloro-7-methoxyquinazoline 2.4 g,(64%).

Example 10

Cis-4-(8-bromo-7-methoxyquinazolin-4-yl)hexahydro-2H-furo[3,2-b]pyrrole:

To a solution of 8-bromo-4-chloro-7-methoxyquinazoline (1.30 g, 4.75mmol) in dry dimethylformamide (20 mL) was addedhexahydro-2H-furo[3,2-b]pyrrole (860 mg, 7.60 mmol) anddiisopropylethylamine (1.84 g, 14.3 mmol). Nitrogen was bubbled throughthe mixture for 5 min and it was heated at 100° C. for 12 hrs under N₂.The mixture was concentrated in vacuo, the residue was dissolved indichloromethane (50 mL). The mixture was adjusted to pH 8 by sat. aq.NaHCO₃. The aqueous layer was extracted with dichloromethane (50 mL).The combined organic phases were dried over Na₂SO₄, filtered andconcentrated. The crude product was purified by chromatography on silicagel using a gradient of dichloromethane and ethyl acetate to give4-(8-bromo-7-methoxyquinazolin-4-yl)hexahydro-2H-furo[3,2-b]pyrrole 1.6g (95%).

The racemate ofcis-4-(8-bromo-7-methoxyquinazolin-4-yl)hexahydro-2H-furo[3,2-b]pyrrole(1.6 g) was purified by SFC (Column: AD 250 mm*50 mm, 10 um) separationand numbered according to the order of elution:

Stereoisomer 1:

651 mg (39.3%)

¹H NMR (CDCl₃, 400 MHz): δ8.70 (s, 1 H), 8.11 (d, J=9.2 Hz, 1 H), 7.12(d, J=9.2 Hz, 1H), 5.16-5.14 (m, 1H), 4.58-4.55 (m, 1H), 4.14-4.08 (m,2H), 4.05 (s, 3 H), 3.94-3.91 (m, 2H), 2.44-2.31 (m, 2H), 2.16-2.15 (m,1H), 2.03-1.95 (m, 1H).

LC-MS (m/z) 350.0 (MH⁺) t_(R) (minutes, method 1)=2.02

[α]_(D) ²⁰+303° (c=0.10, CHCl₃)

Stereoisomer 2:

564 mg (35.2%)

¹H NMR (CDCl₃, 400 MHz): δ8.70 (s, 1 H), 8.11 (d, J=9.2 Hz, 1 H), 7.12(d, J=9.2 Hz, 1H), 5.16-5.14 (m, 1H), 4.58-4.56 (m, 1H), 4.13-4.07 (m,2H), 4.05 (s, 3 H), 3.94-3.90 (m, 2H), 2.44-2.31 (m, 2H), 2.16-2.14 (m,1H), 2.01-1.98 (m, 1H).

LC-MS (m/z) 350.0 (MH⁺) t_(R) (minutes, method 1)=2.02

[α]_(D) ²⁰−233° (c=0.10, CHCl₃)

Example 11

8-Chloro-7-methoxy-N-methyl-N-(3-methyltetrahydrofuran-3-yl)quinazolin-4-amine:

Stereoisomer 1

To an ice-cold solution of stereoisomer 2 of (example 7)8-chloro-7-methoxy-N-(3-methyltetrahydrofuran-3-yl)quinazolin-4-amine(200 mg, 0.681 mmol) in THF (10 mL) was added NaH (60% dispersion inmineral oil) (41 mg, 1.0 mmol). The mixture was stirred at 0° C. for 30min. Then Mel (126 mg, 0.885 mmol) was added at 0° C. and it was stirredat 25° C. for 3 hrs. H₂O (5 mL) was added to the mixture and the THF wasremoved in vacuo. The residue was extracted with dichloromethane (2×20mL). The combined organic phases were washed with H₂O (10 mL), driedover Na₂SO₄, filtered, and concentrated in vacuo. The crude product waspurified by preparative TLC, eluting with dichloromethane/methanol=50/1,to give stereoisomer 1 of8-chloro-7-methoxy-N-methyl-N-(3-methyltetrahydrofuran-3-yl)quinazolin-4-amine156 mg (70.7%).

¹H NMR (CD₃OD, 400 MHz): δ8.49 (s, 1 H), 8.08 (d, J=9.2 Hz, 1 H), 7.39(d, J=9.6 Hz, 1 H), 4.37 (d, J=8.8 Hz, 1 H), 4.05 (s, 3 H), 3.97-3.85(m, 3 H), 3.35 (s, 3 H), 2.47-2.41 (m, 1 H), 2.31-2.27 (m, 1 H), 1.69(s, 3 H).

LC-MS (m/z) 308.1 (MH⁺) t_(R) (minutes, method 1)=1.932

[α]_(D) ²⁰+20.33° (c=0.10, methanol).

Stereoisomer 2

To an ice-cold solution of stereoisomer 1 of (example 7)8-chloro-7-methoxy-N-(3-methyltetrahydrofuran-3-yl)quinazolin-4-amine(200 mg, 0.681 mmol) in THF (10 mL) was added NaH (60% dispersion inmineral oil) (41 mg, 1.0 mmol). The mixture was stirred at 0° C. for 30min and then Mel (126 mg, 0.885 mmol) was added. The mixture was heatedto 25° C. and stirred for 3 hrs. To the reaction mixture was added H₂O(5 mL) and THF was removed in vacuo. The residue was extracted withdichloromethane (2×20 mL). The combined organic phases were washed withwater (10 mL), dried over Na₂SO₄ and concentrated in vacuo. The crudeproduct was purified by preparative TLC, eluting withdichloromethane/methanol=50/1, to give stereoisomer 2 of8-chloro-7-methoxy-N-methyl-N-(3-methyltetrahydrofuran-3-yl)quinazolin-4-amine141 mg (63.9%).

¹H NMR (CD₃OD, 400 MHz): δ8.49 (s, 1 H), 8.08 (d, J=9.2 Hz, 1 H), 7.39(d, J=9.6 Hz, 1 H), 4.37 (d, J=8.8 Hz, 1 H), 4.05 (s, 3 H), 3.97-3.85(m, 3 H), 3.35 (s, 3 H), 2.47-2.44 (m, 1 H), 2.31-2.6 (m, 1 H), 1.68 (s,3 H).

LC-MS (m/z) 308.1 (MH⁺) t_(R) (minutes, method 1)=1.950

[α]_(D) ²⁰−26.33° (c=0.10, methanol).

Example 12

8-Chloro-N-(2,3-dimethyltetrahydrofuran-3-yl)-7-methoxyquinazolin-4-amine:

To a solution of 4,8-dichloro-7-methoxyquinazoline (1.8 g, 7.9 mmol) inDMSO (30 mL) was added 2,3-dimethyltetrahydrofuran-3-amine (905 mg, 7.86mmol) and NaHCO₃ (660 mg, 7.86 mmol). The mixture was heated at 100° C.for 3 hrs and then cooled to 20° C. H₂O (30 mL) was added to themixture, the precipitate was filtered off and washed with water (50 mL),dried and purified by flash chromatography on silica gel using agradient of dichloromethane and methanol to give8-chloro-N-(2,3-dimethyltetrahydrofuran-3-yl)-7-methoxyquinazolin-4-amine(1.2 g, 50

The mixture of all 4 stereoisomers of8-chloro-N-(2,3-dimethyltetrahydrofuran-3-yl)-7-methoxyquinazolin-4-amine2.4 g was purified by SFC (Column: AS 300 mm*50 mm, 10 um). Thestereoisomers were numbered according to their order of elution.

Stereoisomer 1:

400 mg (15.8%)

¹H NMR (CD₃OD, 400 MHz): δ8.47 (s, 1 H), 8.17 (d, J=9.2 Hz, 1 H), 7.38(d, J=8.8 Hz, 1 H), 4.52 (q, J=6.4 Hz, 1 H), 4.04 (s, 3 H), 4.02-3.96(m, 1 H), 3.86 (q, J=8.4 Hz, 1 H), 2.61-2.55 (m, 1 H), 2.19-2.13 (m, 1H), 1.65 (s, 3 H), 1.06 (d, J=6.4 Hz, 3 H).

LC-MS (m/z) 308.1 (MH⁺) t_(R) (minutes, method 5)=1.267

[α]_(D) ²⁰+20.00° (c=0.10, methanol).

Stereoisomer 2:

300 mg (11.9%)

¹H NMR (CD₃OD, 400 MHz): δ8.47 (s, 1 H), 8.16 (d, J=9.2 Hz, 1 H), 7.38(d, J=9.6 Hz, 1 H), 4.51 (q, J=6.4 Hz, 1 H), 4.04 (s, 3 H), 4.02-3.97(m, 1 H), 3.86 (q, J=8.4 Hz, 1 H), 2.61-2.55 (m, 1 H), 2.19-2.13 (m, 1H), 1.65 (s, 3 H), 1.06 (d, J=6.4 Hz, 3 H).

LC-MS (m/z) 308.1 (MH⁺) t_(R) (minutes, method 5)=1.272

[α]_(D) ²⁰−13.33° (c=0.10, methanol).

Stereoisomer 3:

600 mg (23.7%)

¹H NMR (CD₃OD, 400 MHz): δ8.46 (s, 1 H), 8.20 (d, J=9.2 Hz, 1 H), 7.36(d, J=9.2 Hz, 1 H), 4.47 (q, J=6.4 Hz, 1 H), 4.03 (s, 3 H), 3.99-3.90(m, 2 H), 2.71-2.66 (m, 1 H), 2.26-2.21 (m, 1 H), 1.57 (s, 3 H), 1.26(d, J=6.4 Hz, 3 H).

LC-MS (m/z) 308.1 (MH⁺) t_(R) (minutes, method 5)=1.295

[α]_(D) ²⁰−25.33° (c=0.10, methanol).

Stereoisomer 4:

700 mg (27.7%)

¹H NMR (CD₃OD, 400 MHz): δ8.46 (s, 1 H), 8.21 (d, J=9.2 Hz, 1 H), 7.36(d, J=9.2 Hz, 1 H), 4.47 (q, J=6.4 Hz, 1 H), 4.04 (s, 3 H), 3.99-3.90(m, 2 H), 2.71-2.66 (m, 1 H), 2.26-2.21 (m, 1 H), 1.57 (s, 3 H), 1.26(d, J=6.4 Hz, 3 H).

LC-MS (m/z) 308.1 (MH⁺) t_(R) (minutes, method 5)=1.30

[α]_(D) ²⁰+43.67° (c=0.10, methanol).

Example 13

8-Chloro-N-(2,3-dimethyltetrahydrofuran-3-yl)-7-methoxy-N-methylquinazolin-4-amine:

Stereoisomer 1:

To an ice-cold solution of stereoisomer 1 example 12 (200 mg, 0.650mmol) in THF (10 mL) was added NaH (60% dispersion in mineral oil) (39mg, 0.98 mmol). The mixture was stirred at 0° C. for 30 min and then Mel(120 mg, 0.845 mmol) was added. The reaction was allowed to warm to 25°C. and stirred for 3 hrs. H₂O (5 mL) was added to the mixture and theTHF was removed in vacuo. The residue was extracted with dichloromethane(2×20 mL). The combined organic phases were washed with H₂O (10 mL),dried over Na₂SO₄, concentrated in vacuo and purified by preparativeTLC, using dichloromethane/methanol=50/1, to give stereoisomer 1 of8-chloro-N-(2,3-dimethyltetrahydrofuran-3-yl)-7-methoxy-N-methylquinazolin-4-amine(118 mg, 57%).

¹H NMR (CD₃OD, 400 MHz): δ8.54 (s, 1 H), 8.12 (d, J=9.2 Hz, 1 H), 7.46(d, J=9.2 Hz, 1 H), 4.09 (s, 3 H), 4.07-4.04 (m, 1 H), 3.94-3.88 (m, 1H), 3.40 (s, 3 H), 2.66 -2.58 (m, 1 H), 2.26-2.21 (m, 1 H), 1.73 (s, 3H), 0.96 (d, J=6.4 Hz, 3 H).

LC-MS (m/z) 322.2 (MH⁺) t_(R) (minutes, method 5)=1.46

[α]_(D) ²⁰−9.67° (c=0.10, methanol).

Stereoisomer 2:

To an ice-cold solution of stereoisomer 2 example (200 mg, 0.650 mmol)in THF (10 mL) was added NaH (60% dispersion in mineral oil) (39 mg,0.98 mmol). The mixture was stirred at 0° C. for 30 min and then Mel(120 mg, 0.845 mmol) was added. The reaction was stirred at 25° C. for 3hrs and then H₂O (5 mL) was added. THF was removed in vacuo and theresidue extracted with dichloromethane (2×20 mL). The combined organicphases were washed with H₂O (10 mL), dried over Na₂SO₄, and concentratedin vacuo. The crude product was purified by preparative TLC, usingdichloromethane/methanol=50/1, to give stereoisomer 2 of8-chloro-N-(2,3-dimethyltetrahydrofuran-3-yl)-7-methoxy-N-methylquinazolin-4-amine(120 mg, 57%).

¹H NMR (CD₃OD, 400 MHz): δ8.54 (s, 1 H), 8.12 (d, J=9.2 Hz, 1 H), 7.46(d, J=9.2 Hz, 1 H), 4.09 (s, 3 H), 4.07-4.04 (m, 1 H), 3.94-3.88 (m, 1H), 3.40 (s, 3 H), 2.66-2.58 (m, 1 H), 2.25-2.21 (m, 1 H), 1.73 (s, 3H), 0.96 (d, J=6.0 Hz, 3 H).

LC-MS (m/z) 322.2 (MH⁺) t_(R) (minutes, method 5)=1.46

[α]_(D) ²⁰+5.33° (c=0.10, methanol).

Stereoisomer 3:

To an ice-cold solution of stereoisomer 3 example 12 (200 mg, 0.650mmol) in THF (10 mL) was added NaH (60% dispersion in mineral oil) (39mg, 0.98 mmol). The mixture was stirred at 0° C. for 30 min and then Mel(120 mg, 0.845 mmol) was added at 0° C. The reaction was stirred at 25°C. for 3 hrs and then H₂O (5 mL) was added. THF was removed in vacuo andthe residue was extracted with dichloromethane (2×20 mL). The combinedorganic phases were washed with H₂O (10 mL), dried over Na₂SO₄ andconcentrated in vacuo. The crude product was purified by preparativeTLC, using dichloromethane/methanol =50/1, to give stereoisomer 3 of8-chloro-N-(2,3-dimethyltetrahydrofuran-3-yl)-7-methoxy-N-methylquinazolin-4-amine(78 mg, 37%).

¹H NMR (CD₃OD, 400 MHz): δ8.61 (s, 1 H), 8.08 (d, J=9.6 Hz, 1 H), 7.48(d, J=9.6 Hz, 1 H), 4.50-4.47 (m, 1 H) 4.10 (s, 3 H), 3.95-3.91 (m, 1H), 3.88-3.84 (m, 1 H), 3.31 (s, 3 H), 2.67-2.62 (m, 1 H), 2.32-2.26 (m,1 H), 1.65 (s, 3 H), 1.39 (d, J=6.4 Hz, 3 H).

LC-MS (m/z) 322.2 (MH⁺) t_(R) (minutes, method 5)=1.50

[α]_(D) ²⁰−49.33° (c=0.10, methanol).

Stereoisomer 4:

To an ice-cold solution of stereoisomer 4 example 12 (200 mg, 0.650mmol) in THF (10 mL) was added NaH (60% dispersion in oil) (39 mg, 0.98mmol). The mixture was stirred at 0° C. for 30 min and then Mel (120 mg,0.845 mmol) was added. The reaction was stirred at 25° C. for 3 hrs.Then H₂O (5 mL) was added and THF was removed in vacuo. The residue wasextracted with dichloromethane (2×20 mL). The combined organic phaseswere washed with H₂O (10 mL), dried over Na₂SO₄, and concentrated invacuo. The crude product was purified by preparative TLC, usingdichloromethane/methanol=50/1, to give stereoisomer 4 of8-chloro-N-(2,3-dimethyltetrahydrofuran-3-yl)-7-methoxy-N-methylquinazolin-4-amine(92 mg, 44%).

¹H NMR (CD₃OD, 400 MHz): δ8.62 (s, 1 H), 8.08 (d, J=9.6 Hz, 1 H), 7.48(d, J=9.6 Hz, 1 H), 4.50-4.47 (m, 1 H) 4.10 (s, 3 H), 3.95-3.91 (m, 1H), 3.88-3.84 (m, 1 H), 3.32 (s, 3 H), 2.67-2.62 (m, 1 H), 2.32-2.26 (m,1 H), 1.65 (s, 3 H), 1.39 (d, J=7.6 Hz, 3 H).

LC-MS (m/z) 322.2 (MH⁺) t_(R) (minutes, method 5)=1.50

[α]_(D) ²⁰+33.33° (c=0.10, methanol).

Example 14

8-Chloro-7-methoxy-N-methyl-N-(2-methyltetrahydrofuran-3-yl)quinazolin-4-amine:

Stereoisomer 1:

To an ice-cold solution of stereoisomer 1 of example 5(8-chloro-7-methoxy-N-(2-methyltetrahydrofuran-3-yl)quinazolin-4-amine)(250 mg, 0.851 mmol) in THF (10 mL) was added a 60% suspension of NaH inmineral oil (61 mg, 1.5 mmol). The mixture was stirred at 0° C. for 30min and then Mel (181 mg, 1.28 mmol) was added at 0° C. After stirringat 30° C. for 3 hrs H₂O (5 mL) was added to the mixture. THF was removedin vacuo and the residue was extracted with dichloromethane (2×20 mL).The combined organic phases were washed with H₂O (10 mL), dried overNa₂SO₄ and concentrated in vacuo. The crude product was purified bypreparative TLC, using dichloromethane/methanol=50/1, to givestereoisomer 1 of8-chloro-7-methoxy-N-methyl-N-2-methyltetrahydrofuran-3-yl)quinazolin-4-amine(192 mg, 70.

¹H NMR (CDCl₃, 400 MHz): δ8.75 (s, 1 H), 7.92 (d, J=8.8 Hz, 1 H), 7.17(d, J=9.6 Hz, 1 H), 4.82-4.76 (m, 1 H), 4.18 (q, J=6.4 Hz, 1 H), 4.08(s, 3 H), 4.05-4.02 (m, 2 H), 3.29 (s, 3 H), 2.54-2.49 (m, 1 H),2.18-2.11 (m, 1 H), 1.28 (d, J=6.0 Hz, 3 H).

LC-MS (m/z) 308.1 (MH⁺) t_(R) (minutes, method 1)=1.96

[α]_(D) ²⁰−46.00° (c=0.10, methanol). Stereoisomer 2:

To an ice-cold solution of stereoisomer 2 of example 5(8-chloro-7-methoxy-N-(2-methyltetrahydrofuran-3-yl)quinazolin-4-amine)(250 mg, 0.851 mmol) in THF (10 mL) was added a 60% suspension inmineral oil of NaH (61 mg, 1.5 mmol). The mixture was stirred at 0° C.for 30 min and then Mel (181 mg, 1.28 mmol) was added. The reaction wasstirred at 30° C. for 3 hrs before addition of H₂O (5 mL). THF wasremoved in vacuo and the residue was extracted with dichloromethane(2×20 mL). The combined organic phases were washed with H₂O (10 mL),dried over Na₂SO₄, and concentrated in vacuo. The crude product waspurified by preparative TLC, using dichloromethane/methanol=50/1, togive stereoisomer 2 of8-chloro-7-methoxy-N-methyl-N-(-2-methyltetrahydrofuran-3-yl)quinazolin-4-amine(217 mg, 80%).

¹H NMR (CDCl₃, 400 MHz): δ8.70 (s, 1 H), 7.95 (d, J=9.6 Hz, 1 H), 7.14(d, J=9.6 Hz, 1 H), 5.47-5.42 (m, 1 H), 4.20-4.17 (m, 1 H), 4.07 (s, 3H), 4.05-4.02 (m, 2 H), 3.73 (q, J=8.8 Hz, 1 H), 3.38 (s, 3 H),2.47-2.42 (m, 1 H), 2.33-2.30 (m, 1 H), 1.28 (d, J=6.4 Hz, 3 H).

LC-MS (m/z) 308.1 (MH⁺) t_(R) (minutes, method 1)=1.94

[α]_(D) ²⁰−48.00° (c=0.10, methanol).

Stereoisomer 3:

To an ice-cold solution of stereoisomer 3 of example 5(8-chloro-7-methoxy-N-(2-methyltetrahydrofuran-3-yl)quinazolin-4-amine)(160 mg, 0.545 mmol) in THF (10 mL) was added a 60% suspension of NaH inmineral oil (39 mg, 0.98.mmol) and the mixture was stirred at 0° C. for30 min. Mel (116 mg, 0.817 mmmol) was added at 0° C. The reaction wasstirred at 30° C. for 3 hrs and then H₂O (5 mL) was added. THF wasremoved in vacuo and the residue was extracted with dichloromethane(2×20 mL). The combined organic phases were washed with H₂O (10 mL),dried over Na₂SO₄, and concentrated in vacuo. The crude product waspurified by preparative TLC, using dichloromethane/methanol=50/1) togive stereoisomer 3 of 8-chloro-7-methoxy-N-methyl-N-(-2-methyltetrahydrofu ran-3-yl)quinazol in-4-amine

139 mg (81%).

¹H NMR (CDCl₃, 400 MHz): δ8.70 (s, 1 H), 7.95 (d, J=9.6 Hz, 1 H), 7.14(d, J=9.2 Hz, 1 H), 5.47-5.42 (m, 1 H), 4.20-4.16 (m, 1 H), 4.07 (s, 3H), 4.05-4.02 (m, 2 H), 3.75-3.73 (m, 1 H), 3.38 (s, 3 H), 2.47-2.42 (m,1 H), 2.34-2.30 (m, 1 H), 1.28 (d, J=6.0 Hz, 3 H).

LC-MS (m/z) 308.1 (MH⁺) t_(R) (minutes, method 1)=1.96

[α]_(D) ²⁰30 52.67° (c=0.10, methanol).

Stereoisomer 4:

To an ice-cold solution of stereoisomer 4 of example 5(8-chloro-7-methoxy-N-(2-methyltetrahydrofuran-3-yl)quinazolin-4-amine)(200 mg, 0.681 mmol) in THF (10 mL) was added a 60% suspension of NaH inmineral oil (49 mg, 1.2 mmol). The mixture was stirred at 0° C. for 30min and then Mel (145 mg, 1.02 mmol) was added. The reaction was stirredat 30° C. for 3 hrs and then H₂O (5 mL) was added. THF was removed invacuo and the residue was extracted with dichloromethane (2×20 mL). Thecombined organic phases were washed with H₂O (10 mL), dried over Na₂SO₄,and concentrated in vacuo. The crude product was purified by preparativeTLC, dichloromethane/methanol=50/1, to give stereoisomer 4 of8-chloro-7-methoxy-N-methyl-N-(2-methyltetrahydrofuran-3-yl)quinazolin-4-amine184 mg (85%).

¹H NMR (CDCl₃, 400 MHz): δ8.75 (s, 1 H), 7.92 (d, J=9.2 Hz, 1 H), 7.17(d, J=9.2 Hz, 1 H), 4.82-4.76 (m, 1 H), 4.19-4.16 (m, 1 H), 4.08 (s, 3H), 4.05-4.02 (m, 2 H), 3.29 (s, 3 H), 2.54-2.49 (m, 1 H), 2.18-2.11 (m,1 H), 1.28 (d, J=6.4 Hz, 3 H).

LC-MS (m/z) 308.1 (MH⁺) t_(R) (minutes, method 1)=1.94

[α]_(D) ²⁰+35.33° (c=0.10, methanol).

Example 15

8-Fluoro-7-methoxy-N-methyl-N-(3-methyltetrahydrofuran-3-yl)quinazolin-4-amine:

Stereoisomer 1:

To solution of stereoisomer 1 of example 1(8-fluoro-7-methoxy-N-(3-methyltetrahydrofuran-3-yl)quinazolin-4-amine)(200 mg, 0.721 mmol) in THF (4 mL) was added a 60% suspension of NaH inmineral oil (43 mg, 1.1 mmol) at 0° C. After stirring for 30 min thereaction was heated to 20° C. Mel (154 mg, 1.08 mmol) was added and thereaction was stirred for 12 hrs. The reaction was quenched with sat. aq.NH₄Cl (0.5 mL) and concentrated in vacuo. The residue was diluted withdichloromethane (20 mL), washed with brine (10 mL), dried, andconcentrated in vacuo. The crude product was purified by preparativeTLC, using ethyl acetate, to give stereoisomer 1 of8-fluoro-7-methoxy-N-methyl-N-(3-methyltetrahydrofuran-3-yl)quinazolin-4-amine150 mg (70%).

¹H NMR (CDCl₃, 400 MHz): δ8.65 (s, 1H), 7.73 (dd, J=9.6, 2.0 Hz, 1H),7.19 (dd, J=9.6, 8.0 Hz, 1 H), 4.35 (d, J=8.8 Hz, 1 H), 4.07 (s, 3H),4.02-3.88 (m, 3H), 3.31 (s, 3H), 2.41-2.35 (m, 1H), 2.28-2.24 (m, 1H),1.71 (s, 3H).

LC-MS (m/z) 292.1 (MH⁺) t_(R) (minutes, method 1)=1.83

[α]_(D) ²⁰+38.33° (c=0.10, methanol).

Stereoisomer 2:

To a solution of stereoisomer 2 of example 1(8-fluoro-7-methoxy-N-(3-methyltetrahydrofuran-3-yl)quinazolin-4-amine)(200 mg, 0.721 mmol) in THF (4 mL) was added a 60% suspension in mineraloil NaH (43 mg, 1.1 mmol) at 0° C. and the reaction was stirred for 30min before being heated at 20° C. Mel (154 mg, 1.08 mmol) was added andstirring continued for 12 hrs. The solution was quenched with sat. aq.NH₄Cl (1 mL) and concentrated in vacuo. The residue was diluted withdichloromethane (20 mL), washed with brine (3×8 mL), dried over MgSO₄and concentrated in vacuo. The crude product was purified by preparativeTLC, using ethyl acetate, to give stereoisomer 2 of8-fluoro-7-methoxy-N-methyl-N-(3-methyltetrahydrofuran-3-yl)quinazolin-4-amine160 mg (75%).

¹H NMR (CDCl₃, 400 MHz): δ8.65 (s, 1H), 7.73 (dd, J=9.6,1.6 Hz, 1 H),7.18 (dd, J=9.2, 8.0 Hz, 1H), 4.35 (d, J=9.2 Hz, 1H), 4.02 (s, 3H),4.00-3.88 (m, 3H), 3.31 (s, 3H), 2.43-2.35 (m, 1H), 2.28-2.24 (m, 1H),1.71 (s, 3H).

LC-MS (m/z) 292.1 (MH⁺) t_(R) (minutes, method 1)=1.83

[α]_(D) ²⁰31 30.00° (c=0.10, methanol).

Example 16

8-Fluoro-7-methoxy-N-(tetrahydrofuran-3-yl)quinazolin-4-amine:

A solution of 4-chloro-8-fluoro-7-methoxyquinazoline (400 mg, 1.88 mmol)tetrahydrofuran-3-amine (192 mg, 2.26 mmol) and diisopropylethylamine(486 mg, 3.76 mmol) in DMF (10 mL) was stirred at 100° C. for 3 hrs. Thereaction mixture was concentrated in vacuo and purified by flashchromatography on silica gel using a io gradient dichloromethane/ethylacetate to give8-fluoro-7-methoxy-N-(tetrahydrofuran-3-yl)quinazolin-4-amine 360 mg(72%).

The racemate of8-fluoro-7-methoxy-N-(tetrahydrofuran-3-yl)quinazolin-4-amine (360 mg)was purified by SFC (Column: AD-H (250 mm*30 mm,5 um)) separation andnumbered according to the order of elution:

Stereoisomer 1:

150 mg (42%)

¹H NMR (CDCl₃, 400 MHz): δ8.66 (s, 1H), 7.48 (dd, J=9.2, 1.6 Hz, 1H),7.22-7.18 (m, 1H), 5.86 (d, J=6.4 Hz, 1H), 4.99-4.94 (m, 1 H), 4.05-3.99(m, 1H), 3.99 (s, 3H), 3.97-3.96 (m, 1H), 3.91-3.86 (m, 2H), 2.49-2.43(m, 1H), 2.05-2.00 (m, 2H).

LC-MS (m/z) 264.1 (MH⁺) t_(R) (minutes, method 1)=1.72

[α]_(D) ²⁰+29.33° (c=0.10, methanol).

Stereoisomer 2:

150 mg (42%)

¹H NMR (CDCl₃, 400 MHz): δ8.66 (s, 1H), 7.48 (d, J=8.8 Hz, 1H),7.22-7.18 (m, 1H), 5.86 (d, J=6.4 Hz, 1H), 4.99-4.94 (m, 1H), 4.05-4.00(m, 1H), 4.00 (s, 3H), 3.97-3.96 (m, 1H), 3.91-3.88 (m, 2H), 2.49-2.44(m, 1H), 2.05-2.00 (m, 2H).

LC-MS (m/z) 264.1 (MH⁺) t_(R) (minutes, method 1)=1.72

[α]D²⁰−34.67° (c=0.10, methanol).

Example 17

N-(2,3-Dimethyltetrahydrofuran-3-yl)-8-fluoro-7-methoxyquinazolin-4-amine:

To a solution of 4-chloro-8-fluoro-7-methoxyquinazoline (1.00 g, 4.70mmol) in DMSO (15 mL) was added 2,3-dimethyltetrahydrofuran-3-amine (541mg, 4.70 mmol) and NaHCO₃ (395 mg, 4.70 mmol). The mixture was heated at100° C. for 3 hrs and then cooled to 25° C. H₂O (50 mL) was added andthe mixture was extracted with dichloromethane (2×50 mL). The combinedorganic phases were washed with water (2×50 mL), dried over Na₂SO₄, andconcentrated in vacuo. The crude product was purified by flashchromatography on silica gel using a gradient of dichloromethane andmethanol, to giveN-(2,3-dimethyltetrahydrofuran-3-yl)-8-fluoro-7-methoxyquinazolin-4-amine700 mg (51%).

The mixture of all 4 stereoisomers ofN-(2,3-dimethyltetrahydrofuran-3-yl)-8-fluoro-7-methoxyquinazolin-4-amine2.3 g was purified by SFC (Column: Chiral Pak AD, 5 μm, Daicel ChemicalIndustries, Ltd 250×30 mm I.D).

Stereoisomer 3:

300 mg (13%)

¹H NMR (CDCl3, 400 MHz): δ8.66 (s, 1H), 7.43-7.41 (m, 1H), 7.21-7.17 (m,1H), 5.74 (s, 1H), 4.05 (s, 3H), 3.92-3.85 (m, 3H), 2.97-2.91 (m, 1H),2.10-2.03 (m, 1H), 1.71 (s, 3H), 1.36 (d, J=6.4 Hz, 3H).

LC-MS (m/z) 292.1 (MH⁺) t_(R) (minutes, method 1)=1.88

[α]_(D) ²⁰−25.67° (c=0.10, methanol).

Stereoisomer 4:

300 mg (13%)

¹H NMR (CDCl3, 400 MHz): δ8.64 (s, 1H), 7.42-7.39 (m, 1H), 7.19-7.15 (m,1H), 5.71 (s, 1H), 4.02 (s, 3H), 3.89-3.82 (m, 3H), 2.94-2.88 (m, 1H),2.08-2.01 (m, 1H), 1.69 (s, 3H), 1.33 (d, J=6.4 Hz, 3H).

LC-MS (m/z) 292.1 (MH⁺) t_(R) (minutes, method 1)=1.86

[α]_(D) ²⁰+27.33° (c=0.10, methanol)

From the first SFC purification a mixture of stereoisomer 1 and 2 wasobtained. This mixture was subjected to a second purification bySFC(Column: Chiral Pak AS, 5 μm, Daicel Chemical Industries, Ltd 250×30mm I.D.) chromatography to yield:

Stereoisomer 2

600 mg (26%)

¹H NMR (CDCl₃, 400 MHz): δ8.60 (s, 1H), 7.45-7.42 (m, 1H), 7.15-7.11 (m,1H), 5.63 (s, 1H), 4.27 (q, J=6.4 Hz, 1H), 3.99 (s, 3H), 3.95-3.85 (m,2H), 2.72-2.66 (m, 1H), 2.22-2.17 (m, 1H), 1.56 (s, 3H), 1.23 (d, J=6.4Hz, 3H).

LC-MS (m/z) 292.1 (MH⁺) t_(R) (minutes, method 1)=1.90

[α]_(D) ²⁰+41.33° (c=0.10, methanol).

Stereoisomer 1:

600 mg (26%)

¹H NMR (CDCl₃, 400 MHz): δ8.60 (s, 1H), 7.44-7.42 (m, 1H), 7.16-7.12 (m,1H), 5.61 (s, 1H), 4.27 (q, J=6.4 Hz, 1H), 4.00 (s, 3H), 3.99-3.87 (m,2H), 2.73-2.66 (m, 1H), 2.22-2.18 (m, 1H), 1.57 (s, 3H), 1.23 (d, J=6.0Hz, 3H).

LC-MS (m/z) 292.1 (MH⁺) t_(R) (minutes, method 1)=1.89

[α]_(D) ²⁰−23.67° (c=0.10, methanol).

Example 18

8-Fluoro-7-methoxy-N-methyl-N-(2-methyltetrahydrofuran-3-yl)quinazolin-4-amine

Stereoisomer 1:

To a solution of stereoisomer 2 of example 3(N-(2,3-dimethyltetrahydrofuran-3-yl)-8-fluoro-7-methoxyquinazolin-4-amine)(150 mg, 0.540 mmol) in dry THF (5 mL) was added a 60% suspension of NaHin mineral oil (32 mg, 0.81 mmol) at 0° C. under N₂. The mixture wasstirred at 0° C. for 30 min, then CH₃I (92 mg, 0.65 mmol) was added. Thereaction was stirred for 2 hrs at 0° C. before addition of sat. aq.NH₄Cl (5 mL). The crude reaction mixture was extracted with ethylacetate (3×10 mL). The combined organic phases were washed with brine (5mL), dried over Na₂SO₄, and concentrated in vacuo. The residue waspurified by flash chromatography using a gradient of petroleum ether andethyl acetate to give stereoisomer 1 of8-fluoro-7-methoxy-N-methyl-N-(2-methyltetrahydrofuran-3-yl)quinazolin-4-amine135 mg (86%).

¹H NMR (CDCl₃, 400 MHz): δ8.62 (s, 1H), 7.79 (dd, J=9.6, 2.0 Hz, 1H),7.17-7.13 (m, 1H), 5.50-5.45 (m, 1H), 4.20-4.16 (m, 1H), 4.07 (s, 3H),4.04-4.03 (m, 1H), 3.77-3.71 (m, 1H), 3.39 (s, 3H), 2.46-2.42 (m, 1H),2.33-2.29 (m, 1H), 1.29 (d, J=6.8 Hz, 3H).

LC-MS (m/z) 292.1 (MH⁺) t_(R) (minutes, method 2)=1.80

[α]_(D) ²⁰+43.00° (c=0.10, methanol).

Stereoisomer 2:

To a solution of stereoisomer 1 of example 3(N-(2,3-dimethyltetrahydrofuran-3-yl)-8-fluoro-7-methoxyquinazolin-4-amine)(150 mg, 0.540 mmol) in THF (5 mL) was added a 60% suspension of NaH inmineral oil (32 mg, 0.81 mmol) at 0° C. under N₂. The mixture wasstirred for 30 min at 0° C., and then methyliodide (92 mg, 0.65 mmol)was added. Stirring was continued for 2 hrs at 0° C. and then sat. aq.NH₄Cl (5 mL) was added. The mixture was extracted with ethyl acetate(333 10 mL). The combined organic phases were washed with brine (5 mL),dried over Na₂SO₄, and concentrated in vacuo. The crude product waspurified by flash chromatography using a gradient of petroleum ether andethyl acetate to give stereoisomer 2 of8-fluoro-7-methoxy-N-methyl-N-(2-methyltetrahydrofuran-3-yl)quinazolin-4-amine130 mg (82.5%).

¹H NMR (CDCl₃, 400 MHz): δ8.67 (s, 1H), 7.76 (d, J=9.6 Hz, 1H),7.20-7.16 (m, 1H), 4.83 (brs, 1H), 4.19-4.16 (m, 1H), 4.07-4.02 (m, 5H),3.31 (s, 3H), 2.50 (brs, 1H), 2.13 (brs, 1H), 1.30 (d, J=6.0 Hz, 3H).

LC-MS (m/z) 292.1 (MH⁺) t_(R) (minutes, method 2)=1.82

[α]_(D) ²⁰−30.00° (c=0.10, methanol).

Stereoisomer 3:

To a solution of stereoisomer 3 of example 3(N-(2,3-dimethyltetrahydrofuran-3-yl)-8-fluoro-7-methoxyquinazolin-4-amine)(150 mg, 0.540 mmol) in THF (5 mL) was added a 60% suspension of NaH inmineral oil (32 mg, 0.81 mmol) at 0° C. under N₂ and the mixture wasstirred for 30 min. Methyliodide (77 mg, 0.54 mmol) was added at 0° C.and stirring was continued for 2 hrs at 0° C. The reaction was quenchedby sat. aq. NH₄Cl (5 mL) and then extracted with ethyl acetate (3×10mL). The combined organic phases were washed with brine (5 mL), driedover Na₂SO₄ and concentrated in vacuo. The residue was purified by flashchromatography using a gradient of petroleum ether and ethyl acetate togive stereoisomer 3 of8-fluoro-7-methoxy-N-methyl-N-(2-methyltetrahydrofuran-3-yl)quinazolin-4-amine(110 mg (69.8%).

¹H NMR (CDCl₃, 400 MHz): δ8.61 (s, 1H), 7.79 (dd, J=9.6, 2.0 Hz, 1H),7.17-7.13 (m, 1H), 5.49-5.45 (m, 1H), 4.21-4.16 (m, 1H), 4.06 (s, 3H),4.04-4.02 (m, 1H), 3.77-3.73 (m, 1H), 3.39 (s, 3H), 2.46-2.42 (m, 1H),2.33-2.29 (m, 1H), 1.29 (d, J=6.4 Hz, 3H).

LC-MS (m/z) 292.1 (MH⁺) t_(R) (minutes, method 2)=1.81

[α]_(D) ²⁰31 73.00° (c=0.10,methanol).

Stereoisomer 4:

To a solution of stereoisomer 4 of example 3(N-(2,3-dimethyltetrahydrofuran-3-yl)-8-fluoro-7-methoxyquinazolin-4-amine)(150 mg, 0.541 mmol) in THF (5 mL) was added a 60% suspension of NaH inmineral oil (32 mg, 0.81 mmol) at 0° C. under N₂ and the mixture wasstirred for 30 min. Then methyliodide (92 mg, 0.65 mmol) stirring wascontinued for 2 hrs at 0° C. The reaction was quenched by addition ofsat. aq. NH₄Cl (5 mL). The reaction was extracted with ethyl acetate(3×10 mL). The combined organic phases were washed with brine (5 mL),dried over Na₂SO₄ and concentrated in vacuo. The crude product waspurified by flash chromatography using a gradient of petroleum ether andethyl acetate to give give stereoisomer 4 of8-fluoro-7-methoxy-N-methyl-N-(2-methyltetrahydrofuran-3-yl)quinazolin-4-amine 120 mg (76.2%).

¹H NMR (CDCl₃, 400 MHz): δ8.66 (s, 1H), 7.76 (dd, J=9.6, 2.0 Hz, 1H),7.20-7.16 (m, 1H), 4.86-4.81 (m, 1H), 4.19-4.14 (m, 1H), 4.07 (s, 3H),4.06-4.02 (m, 2H), 3.31 (s, 3H), 2.54-2.48 (m, 1H), 2.17-2.10 (m, 1H),1.30 (d, J=6.4 Hz, 3H).

LC-MS (m/z) 292.1 (MH⁺) t_(R) (minutes, method 2)=1.82

[α]_(D) ²⁰+90.33° (c=0.10, methanol).

Example 19

N-(2,3-Dimethyltetrahydrofuran-3-yl)-8-fluoro-7-methoxy-N-methylquinazolin-4-amine:

Stereoisomer 1:

To an ice-cold solution of stereoisomer 3 of example 17 of(N-(2,3-dimethyltetrahydrofuran-3-yl)-8-fluoro-7-methoxyquinazolin-4-amine)(200 mg, 0.687 mmol) in THF (10 mL) was added a 60% dispersion of NaH inmineral oil (55 mg, 1.4 mmol). The mixture was stirred at 0° C. for 30min and then Mel (146 mg, 1.03 mmol) was added. The reaction was warmedto 30° C. and stirred for 2 hrs. H₂O (5 mL) was added and the THF wasremoved in vacuo. The residue was extracted with dichloromethane (2×20mL). The combined organic phases were washed with H₂O (10 mL), driedover Na₂SO₄ and concentrated in vacuo. The crude product was purified bypreparative TLC, using petroleum ether and ethyl acetate 1/1, to givestereoisomer 1 of N-(2,3-dimethyltetrahydrofuran-3-yl)-8-fluoro-7-methoxy-N-methylquinazolin-4-amine

127 mg (60.4%)

¹H NMR (CDCl₃, 400 MHz): δ8.66 (s, 1H), 7.71 (dd, J=9.2, 2.0 Hz, 1H),7.21-7.17 (m, 1H), 4.81 (q, J=6.4 Hz, 1H), 4.06 (s, 3H), 4.04-4.01 (m,1H), 3.94-3.87 (m, 1H), 3.31 (s, 3H), 2.48-2.40 (m, 1H), 2.17-2.13 (m,1H), 1.71 (s, 3H), 0.93 (d, J=6.4 Hz, 3H).

LC-MS (m/z) 306.2 (MH⁺) t_(R) (minutes, method 1)=1.89

[α]_(D) ²⁰−8.00° (c=0.10, methanol).

Stereoisomer 2:

To an ice-cold solution of stereoisomer 2 of example 17(N-(2,3-dimethyltetrahydrofuran-3-yl)-8-fluoro-7-methoxyquinazolin-4-amine)(200 mg, 0.687 mmol) in THF (10 mL) was added a 60% suspension of NaH inmineral oil (55 mg, 1.3 mmol). The reaction was stirred at 0° C. for 30min and then Mel (146 mg, 1.03 mmol) was added. The reaction was thenheated to 30° C. and stirred for 2 hrs. H₂O (5 mL) was added to themixture and THF was removed in vacuo. The residue was extracted withdichloromethane (2×20 mL). The combined organic phases were washed withH₂O (10 mL), dried over Na₂SO₄ and concentrated in vacuo. The crudeproduct was purified by preparative TLC, using petroleum ether and ethylacetate 1/1 to give stereoisomer 2 ofN-(2,3-dimethyltetrahydrofuran-3-yl)-8-fluoro-7-methoxy-N-methylquinazolin-4-amine.

70 mg (33%)

¹H NMR (CDCl₃, 400 MHz): δ8.72 (s, 1H), 7.71 (dd, J=9.6, 2.0 Hz, 1H),7.22-7.18 (m, 1H), 4.38-4.35 (m, 1H), 4.06 (s, 3H), 3.93-3.89 (m, 1H),3.84-3.80 (m, 1H), 3.22 (s, 3H), 2.54-2.50 (m, 1H), 2.30-2.25 (m, 1H),1.60 (s, 3H), 1.37 (d, J=6.0 Hz, 3H).

LC-MS (m/z) 306.2 (MH⁺) t_(R) (minutes, method 1)=1.93

[α]_(D) ²⁰+38.00° (c=0.10, methanol).

Stereoisomer 3:

To an ice-cold solution of stereoisomer 4 of example 17(N-(2,3-dimethyltetrahydrofuran-3-yl)-8-fluoro-7-methoxyquinazolin-4-amine)(200 mg, 0.687 mmol) in THF (10 mL) was added a 60% suspension of NaH inmineral oil (55 mg, 1.4 mmol). The mixture was stirred at 0° C. for 30min and then methyliodide (146 mg, 1.03 mmol) was added. The reactionwas then heated to 30° C. and stirred for 2 hrs. H₂O (5 mL) was added tothe mixture and THF was removed in vacuo. The residue was extracted withdichloromethane (2×20 mL). The combined organic phases were washed withwater (10 mL), dried over Na₂SO₄ and concentrated in vacuo. The crudeproduct was purified by preparative TLC, using petroleum ether and ethylacetate 1/1, to give give stereoisomer 3 ofN-(2,3-dimethyltetrahydrofuran-3-yl)-8-fluoro-7-methoxy-N-methylquinazolin-4-amine.

103 mg (49.2%)

¹H NMR (CDCl₃, 400 MHz): δ8.66 (s, 1H), 7.72 (dd, J=9.2, 1.6 Hz, 1H),7.21-7.17 (m, 1H), 4.84-4.80 (m, 1H), 4.06 (s, 3H), 4.04-4.01 (m, 1H),3.94-3.89 (m, 1H), 3.31 (s, 3H), 2.48-2.40 (m, 1H), 2.17-2.13 (m, 1H),1.71 (s, 3H), 0.93 (d, J=6.4 Hz, 3H).

LC-MS (m/z) 306.2 (MH⁺) t_(R) (minutes, method 1)=1.88

[α]_(D) ²⁰+13.00° (c=0.10, methanol).

Stereoisomer 4:

To an ice-cold solution of stereoisomer 1 of example 17(N-(2,3-dimethyltetrahydrofuran-3-yl)-8-fluoro-7-methoxyquinazolin-4-amine)(200 mg, 0.687 mmol) in THF (10 mL) was added a 60% suspension of NaH(55 mg, 1.4 mmol). The reaction was stirred at 0° C. for 30 min and thenmethyliodide (146 mg, 1.03 mmol) was added. The mixture was allowed towarm to 30° C. and stirred for 2 hrs. H₂O (5 mL) was added to themixture and THF was removed in vacuo. The residue was extracted withdichloromethane (2×20 mL). The combined organic phases were washed withH₂O (10 mL), dried over Na₂SO₄ and concentrated in vacuo. The crudeproduct was purified by preparative TLC, using petroleum ether and ethylacetate=1/1, to give stereoisomer 4 ofN-(2,3-dimethyltetrahydrofuran-3-yl)-8-fluoro-7-methoxy-N-methylquinazolin-4-amine.

73 mg (35%)

¹H NMR (CDCl₃, 400 MHz): δ8.72 (s, 1H), 7.72 (dd, J=9.2, 2.0 Hz, 1H),7.22-7.18 (m, 1H), 4.39-4.35 (m, 1H), 4.06 (s, 3H), 3.92-3.89 (m, 1H),3.84-3.80 (m, 1H), 3.22 (s, 3H), 2.54-2.50 (m, 1H), 2.30-2.25 (m, 1H),1.60 (s, 3H), 1.37 (d, J=6.4 Hz, 3H).

LC-MS (m/z) 306.2 (MH⁺) t_(R) (minutes, method 1)=1.90

[α]_(D) ²⁰−54.33° (c=0.10, methanol).

PDE1 Inhibition Assay

PDE1A, PDE1B and PDE1C assays were performed as follows: the assays wasperformed in 60 μL samples containing a fixed amount of the PDE1 enzym1(sufficient to convert 20-25% of the cyclic nucleotide substrate), abuffer (50 mM HEPES pH 7.6; 10 mM MgCl₂; 0.02% Tween20), 0.1 mg/ml BSA,15 nM tritium labelled cAMP and varying amounts of inhibitors. Reactionswere initiated by addition of the cyclic nucleotide substrate, andreactions were allowed to proceed for 1 h at room temperature beforebeing terminated through mixing with 20 μL (0.2 mg) yttrium silicate SPAbeads (PerkinElmer). The beads were allowed to settle for 1 h in thedark before the plates were counted in a Wallac 1450 Microbeta counter.The measured signals were converted to activity relative to anuninhibited control (100%) and IC₅₀ values were calculated using XlFit(model 205, IDBS).

1-13. (canceled)
 14. A method of treating a neurodegenerative disorderor a psychiatric disorder in a subject, comprising administering to thesubject a therapeutically effective amount of a compound of formula (I):

or a pharmaceutically acceptable acid addition salt, racemic mixture,enantiomer and/or optical isomer, polymorphic form, or tautomeric formthereof; wherein X is halogen; R₁ is selected from the group consistingof H and C₁-C₃ alkyl, wherein the alkyl optionally is substituted one,two or three times with fluorine; R2 is selected from the groupconsisting of H and C₁-C₄ alkyl; wherein the C₁-C₄ alkyl optionally issubstituted one or more times with one or more substituentsindependently selected from the group consisting of phenyl, monocyclic5- or 6-membered heteroaryl, C₃-C₆ cycloalkyl, fluorine, chlorine, and−OR₁₀; or R₂ together with R₉ and the atoms connecting them form asaturated five membered ring; R₃ is selected from the group consistingof H and C₁-C₆ alkyl; wherein the C₁-C₆ alkyl optionally is substitutedone or more times with one or more substituents independently selectedfrom the group consisting of phenyl, monocyclic 5- or 6-memberedheteroaryl, C₃-C₆ cycloalkyl, fluorine, chlorine, and —OR₁₀; R₄ and R₅independently are selected from the group consisting of H, C₁-C₆ alkyl,C₃-C₆ cycloalkyl, fluorine, chlorine, hydroxy and —OR₁₀; wherein theC₁-C₆ alkyl optionally is substituted one or more times with one or moresubstituents independently selected from the group consisting of phenyl,monocyclic 5- or 6-membered heteroaryl, C₃-C₆ cycloalkyl, fluorine,chlorine, and —OR₁₀; R₆ and R₇ independently are selected from the groupconsisting of H and C₁-C₆ alkyl; wherein the C₁-C₆ alkyl optionally issubstituted one or more times with one or more substituentsindependently selected from the group consisting of C₃-C₆ cycloalkyl,fluorine, chlorine, and —OR₁₀; R₈ and R₉ independently are selected fromthe group consisting of H and C₁-C₆ alkyl wherein R₉, when R₉ is a C₁-C₆alkyl, may form a saturated aliphatic five membered ring with R₂;wherein the C₁-C₆ alkyl optionally is substituted one or more times withone or more substituents independently selected from the groupconsisting of C₃-C₆ cycloalkyl, fluorine, chlorine, and —OR₁₀; and eachR₁₀ independently is C₁-C₅ alkyl.
 15. The method according to claim 14,wherein R₂ is H or —CH₃.
 16. The method according to claim 14, whereinat least one of R₆ and R₇ is H.
 17. The method according to claim 16,wherein both R₆ and R₇ are H.
 18. The method according to claim 14,wherein at least four of R₃ to R₉ are H.
 19. The method according toclaim 14, wherein R₂ and R₉ form a five-membered saturated aliphaticring.
 20. The method according to claim 14, wherein when any of R₃, R₄or R₅ are alkyl, then at most one of them is substituted at most oncewith phenyl or monocyclic 5- or 6-membered heteroaryl.
 21. The method ofclaim 14, wherein X is fluorine.
 22. The method of claim 14, wherein Xis chlorine.
 23. A method according to claim 14, comprisingadministering to the subject a therapeutically effective amount of acompound selected from the group consisting of:8-fluoro-7-methoxy-N-(3-methyltetrahydrofuran-3-yl)quinazolin-4-amine;8-fluoro-7-methoxy-N-methyl-N-(tetrahydrofuran-3-yl)quinazolin-4-amine;8-chloro-7-methoxy-N-(tetrahydrofuran-3-yl)quinazolin-4-amine;8-fluoro-7-methoxy-N-(2-methyltetrahydrofuran-3-yl)quinazolin-4-amine;8-chloro-7-methoxy-N-(2-methyltetrahydrofuran-3-yl)quinazolin-4-amine;8-chloro-7-methoxy-N-methyl-N-(tetrahydrofuran-3-yl)quinazolin-4-amine;8-chloro-7-methoxy-N-(3-methyltetrahydrofuran-3-yl)quinazolin-4-amine;cis-4-(8-fluoro-7-methoxyquinazolin-4-yl)hexahydro-2H-furo[3,2-b]pyrrole;cis-4-(8-chloro-7-methoxyquinazolin-4-yl)hexahydro-2H-furo[3,2-b]pyrrole;cis-4-(8-bromo-7-methoxyquinazolin-4-yl)hexahydro-2H-furo[3,2-b]pyrrole;8-chloro-7-methoxy-N-methyl-N-(3-methyltetrahydrofuran-3-yl)quinazolin-4-amine;8-chloro-N-(2,3-dimethyltetrahydrofuran-3-yl)-7-methoxyquinazolin-4-amine;8-chloro-N-(2,3-dimethyltetrahydrofuran-3-yl)-7-methoxy-N-methylquinazolin-4-amine;8-chloro-7-methoxy-N-methyl-N-(2-methyltetrahydrofuran-3-yl)quinazolin-4-amine;8-fluoro-7-methoxy-N-methyl-N-(3-methyltetrahydrofuran-3-yl)quinazolin-4-amine;8-fluoro-7-methoxy-N-(tetrahydrofuran-3-yl)quinazolin-4-amine;N-(2,3-dimethyltetrahydrofuran-3-yl)-8-fluoro-7-methoxyquinazolin-4-amine;8-fluoro-7-methoxy-N-methyl-N-(2-methyltetrahydrofuran-3-yl)quinazolin-4-amine;N-(2,3-dimethyltetrahydrofuran-3-yl)-8-fluoro-7-methoxy-N-methylquinazolin-4-amine;and pharmaceutically acceptable acid addition salts thereof.
 24. Themethod of claim 14, wherein the disorder is a neurodegenerativedisorder.
 25. The method of claim 24, wherein the neurodegenerativedisorder is selected from the group consisting of Alzheimer's Disease,Parkinson's Disease and Huntington's Disease.
 26. The method of claim14, wherein the disorder is a psychiatric disorder.
 27. The method ofclaim 26, wherein the psychiatric disorder is selected from AttentionDeficit Hyperactivity Disorder (ADHD), depression, narcolepsy andcognitive impairment associated with schizophrenia (CIAS).
 28. Themethod of claim 27, wherein the psychiatric disorder is ADHD.
 29. Themethod of claim 14, wherein the compound of formula (I), or thepharmaceutically acceptable acid addition salt, racemic mixture,enantiomer and/or optical isomer, polymorphic form, or tautomeric formthereof is administered to the subject in combination withpharmaceutically acceptable carriers, diluents or excipients.
 30. Themethod of claim 14, wherein the compound of formula (I) or thepharmaceutically acceptable acid addition salt, racemic mixture,enantiomer and/or optical isomer, polymorphic form, or tautomeric formthereof is administered in combination with one or more other activeingredients.
 31. The method of claim 30, wherein the active ingredientis a neuroleptic agent.
 32. The method of claim 14, wherein saidtreating comprises inhibiting phosphodiesterase 1 (PDE1) in the subject.